EP4346826A1 - Combination therapies - Google Patents
Combination therapiesInfo
- Publication number
- EP4346826A1 EP4346826A1 EP22811968.1A EP22811968A EP4346826A1 EP 4346826 A1 EP4346826 A1 EP 4346826A1 EP 22811968 A EP22811968 A EP 22811968A EP 4346826 A1 EP4346826 A1 EP 4346826A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- inhibitor
- kras
- pharmaceutically acceptable
- ethyl
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002648 combination therapy Methods 0.000 title abstract description 15
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 149
- 229940126271 SOS1 inhibitor Drugs 0.000 claims abstract description 142
- 229940125399 kras g12c inhibitor Drugs 0.000 claims abstract description 127
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 103
- 238000000034 method Methods 0.000 claims abstract description 94
- 201000011510 cancer Diseases 0.000 claims abstract description 83
- 102200006538 rs121913530 Human genes 0.000 claims abstract description 76
- 150000003839 salts Chemical class 0.000 claims description 202
- PEMUGDMSUDYLHU-ZEQRLZLVSA-N 2-[(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-[[(2S)-1-methylpyrrolidin-2-yl]methoxy]-6,8-dihydro-5H-pyrido[3,4-d]pyrimidin-4-yl]-1-(2-fluoroprop-2-enoyl)piperazin-2-yl]acetonitrile Chemical compound ClC=1C=CC=C2C=CC=C(C=12)N1CC=2N=C(N=C(C=2CC1)N1C[C@@H](N(CC1)C(C(=C)F)=O)CC#N)OC[C@H]1N(CCC1)C PEMUGDMSUDYLHU-ZEQRLZLVSA-N 0.000 claims description 139
- 229940124988 adagrasib Drugs 0.000 claims description 139
- 150000001875 compounds Chemical class 0.000 claims description 117
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 69
- 210000004027 cell Anatomy 0.000 claims description 62
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 59
- 238000011282 treatment Methods 0.000 claims description 40
- 230000000694 effects Effects 0.000 claims description 36
- 239000003112 inhibitor Substances 0.000 claims description 34
- 230000004614 tumor growth Effects 0.000 claims description 27
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
- 230000001965 increasing effect Effects 0.000 claims description 25
- 230000005764 inhibitory process Effects 0.000 claims description 24
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 21
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 claims description 17
- 230000035945 sensitivity Effects 0.000 claims description 17
- 208000009956 adenocarcinoma Diseases 0.000 claims description 16
- 206010025323 Lymphomas Diseases 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 13
- 201000009030 Carcinoma Diseases 0.000 claims description 12
- 206010039491 Sarcoma Diseases 0.000 claims description 12
- 230000004083 survival effect Effects 0.000 claims description 12
- 206010041823 squamous cell carcinoma Diseases 0.000 claims description 10
- 206010024612 Lipoma Diseases 0.000 claims description 8
- 230000002401 inhibitory effect Effects 0.000 claims description 8
- ORMUFBSBLPMWNO-MRXNPFEDSA-N 3-[(1R)-1-[[6-fluoro-4-methyl-7-(4-methylpiperazin-1-yl)phthalazin-1-yl]amino]ethyl]-2-methylbenzonitrile Chemical compound C[C@@H](NC1=NN=C(C)C2=CC(F)=C(C=C12)N1CCN(C)CC1)C1=CC=CC(C#N)=C1C ORMUFBSBLPMWNO-MRXNPFEDSA-N 0.000 claims description 7
- 229940124647 MEK inhibitor Drugs 0.000 claims description 7
- 231100000682 maximum tolerated dose Toxicity 0.000 claims description 7
- 201000008808 Fibrosarcoma Diseases 0.000 claims description 6
- 206010043276 Teratoma Diseases 0.000 claims description 6
- 206010016629 fibroma Diseases 0.000 claims description 6
- 201000011066 hemangioma Diseases 0.000 claims description 6
- 206010073071 hepatocellular carcinoma Diseases 0.000 claims description 5
- 210000004072 lung Anatomy 0.000 claims description 5
- 201000001441 melanoma Diseases 0.000 claims description 5
- 201000003076 Angiosarcoma Diseases 0.000 claims description 4
- 208000032612 Glial tumor Diseases 0.000 claims description 4
- 206010018338 Glioma Diseases 0.000 claims description 4
- 208000002927 Hamartoma Diseases 0.000 claims description 4
- 208000001258 Hemangiosarcoma Diseases 0.000 claims description 4
- 208000007766 Kaposi sarcoma Diseases 0.000 claims description 4
- 208000018142 Leiomyosarcoma Diseases 0.000 claims description 4
- 208000034578 Multiple myelomas Diseases 0.000 claims description 4
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 claims description 4
- 206010035226 Plasma cell myeloma Diseases 0.000 claims description 4
- 208000008383 Wilms tumor Diseases 0.000 claims description 4
- 208000002458 carcinoid tumor Diseases 0.000 claims description 4
- 208000006990 cholangiocarcinoma Diseases 0.000 claims description 4
- 201000010260 leiomyoma Diseases 0.000 claims description 4
- 206010027191 meningioma Diseases 0.000 claims description 4
- 201000008968 osteosarcoma Diseases 0.000 claims description 4
- 210000002307 prostate Anatomy 0.000 claims description 4
- 210000004556 brain Anatomy 0.000 claims description 3
- 201000009409 embryonal rhabdomyosarcoma Diseases 0.000 claims description 3
- 230000002496 gastric effect Effects 0.000 claims description 3
- 230000002489 hematologic effect Effects 0.000 claims description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 3
- 210000000496 pancreas Anatomy 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 3
- 208000024893 Acute lymphoblastic leukemia Diseases 0.000 claims description 2
- 208000014697 Acute lymphocytic leukaemia Diseases 0.000 claims description 2
- 206010001233 Adenoma benign Diseases 0.000 claims description 2
- 206010003571 Astrocytoma Diseases 0.000 claims description 2
- 208000010839 B-cell chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 206010004146 Basal cell carcinoma Diseases 0.000 claims description 2
- 206010073106 Bone giant cell tumour malignant Diseases 0.000 claims description 2
- 208000009458 Carcinoma in Situ Diseases 0.000 claims description 2
- 201000005262 Chondroma Diseases 0.000 claims description 2
- 208000005243 Chondrosarcoma Diseases 0.000 claims description 2
- 201000009047 Chordoma Diseases 0.000 claims description 2
- 208000006332 Choriocarcinoma Diseases 0.000 claims description 2
- 206010048832 Colon adenoma Diseases 0.000 claims description 2
- 206010010356 Congenital anomaly Diseases 0.000 claims description 2
- 208000007033 Dysgerminoma Diseases 0.000 claims description 2
- 208000000471 Dysplastic Nevus Syndrome Diseases 0.000 claims description 2
- 201000009051 Embryonal Carcinoma Diseases 0.000 claims description 2
- 206010014967 Ependymoma Diseases 0.000 claims description 2
- 208000006168 Ewing Sarcoma Diseases 0.000 claims description 2
- 208000007659 Fibroadenoma Diseases 0.000 claims description 2
- 206010053717 Fibrous histiocytoma Diseases 0.000 claims description 2
- 208000000527 Germinoma Diseases 0.000 claims description 2
- 208000007569 Giant Cell Tumors Diseases 0.000 claims description 2
- 201000005409 Gliomatosis cerebri Diseases 0.000 claims description 2
- 206010018404 Glucagonoma Diseases 0.000 claims description 2
- 206010018691 Granuloma Diseases 0.000 claims description 2
- 206010019629 Hepatic adenoma Diseases 0.000 claims description 2
- 208000017604 Hodgkin disease Diseases 0.000 claims description 2
- 208000010747 Hodgkins lymphoma Diseases 0.000 claims description 2
- 208000005045 Interdigitating dendritic cell sarcoma Diseases 0.000 claims description 2
- 208000002260 Keloid Diseases 0.000 claims description 2
- 208000002404 Liver Cell Adenoma Diseases 0.000 claims description 2
- 208000031422 Lymphocytic Chronic B-Cell Leukemia Diseases 0.000 claims description 2
- 208000006644 Malignant Fibrous Histiocytoma Diseases 0.000 claims description 2
- 208000000172 Medulloblastoma Diseases 0.000 claims description 2
- 206010027406 Mesothelioma Diseases 0.000 claims description 2
- 201000003793 Myelodysplastic syndrome Diseases 0.000 claims description 2
- 208000014767 Myeloproliferative disease Diseases 0.000 claims description 2
- 206010029260 Neuroblastoma Diseases 0.000 claims description 2
- 201000004404 Neurofibroma Diseases 0.000 claims description 2
- 201000010133 Oligodendroglioma Diseases 0.000 claims description 2
- 208000010191 Osteitis Deformans Diseases 0.000 claims description 2
- 208000000035 Osteochondroma Diseases 0.000 claims description 2
- 208000027067 Paget disease of bone Diseases 0.000 claims description 2
- 208000007641 Pinealoma Diseases 0.000 claims description 2
- 208000006664 Precursor Cell Lymphoblastic Leukemia-Lymphoma Diseases 0.000 claims description 2
- 201000004681 Psoriasis Diseases 0.000 claims description 2
- 201000000582 Retinoblastoma Diseases 0.000 claims description 2
- 208000005678 Rhabdomyoma Diseases 0.000 claims description 2
- 201000010208 Seminoma Diseases 0.000 claims description 2
- 208000000097 Sertoli-Leydig cell tumor Diseases 0.000 claims description 2
- 208000015778 Undifferentiated pleomorphic sarcoma Diseases 0.000 claims description 2
- 208000009311 VIPoma Diseases 0.000 claims description 2
- 206010048214 Xanthoma Diseases 0.000 claims description 2
- 206010048215 Xanthomatosis Diseases 0.000 claims description 2
- 230000001154 acute effect Effects 0.000 claims description 2
- 208000002718 adenomatoid tumor Diseases 0.000 claims description 2
- 210000004100 adrenal gland Anatomy 0.000 claims description 2
- 201000007434 ampulla of Vater carcinoma Diseases 0.000 claims description 2
- 208000001119 benign fibrous histiocytoma Diseases 0.000 claims description 2
- 210000003445 biliary tract Anatomy 0.000 claims description 2
- 239000008280 blood Substances 0.000 claims description 2
- 210000004369 blood Anatomy 0.000 claims description 2
- 208000016738 bone Paget disease Diseases 0.000 claims description 2
- 210000000988 bone and bone Anatomy 0.000 claims description 2
- 201000009480 botryoid rhabdomyosarcoma Diseases 0.000 claims description 2
- 201000003149 breast fibroadenoma Diseases 0.000 claims description 2
- 208000003362 bronchogenic carcinoma Diseases 0.000 claims description 2
- 201000002143 bronchus adenoma Diseases 0.000 claims description 2
- 208000011825 carcinoma of the ampulla of vater Diseases 0.000 claims description 2
- 230000000747 cardiac effect Effects 0.000 claims description 2
- 201000005217 chondroblastoma Diseases 0.000 claims description 2
- 230000001684 chronic effect Effects 0.000 claims description 2
- 208000032852 chronic lymphocytic leukemia Diseases 0.000 claims description 2
- 208000009060 clear cell adenocarcinoma Diseases 0.000 claims description 2
- 201000010305 cutaneous fibrous histiocytoma Diseases 0.000 claims description 2
- 208000035250 cutaneous malignant susceptibility to 1 melanoma Diseases 0.000 claims description 2
- 230000002357 endometrial effect Effects 0.000 claims description 2
- 210000003238 esophagus Anatomy 0.000 claims description 2
- 201000010175 gallbladder cancer Diseases 0.000 claims description 2
- 201000007487 gallbladder carcinoma Diseases 0.000 claims description 2
- 208000015419 gastrin-producing neuroendocrine tumor Diseases 0.000 claims description 2
- 201000000052 gastrinoma Diseases 0.000 claims description 2
- 201000003115 germ cell cancer Diseases 0.000 claims description 2
- 208000005017 glioblastoma Diseases 0.000 claims description 2
- 208000006359 hepatoblastoma Diseases 0.000 claims description 2
- 201000002735 hepatocellular adenoma Diseases 0.000 claims description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 claims description 2
- 201000004933 in situ carcinoma Diseases 0.000 claims description 2
- 206010022498 insulinoma Diseases 0.000 claims description 2
- 210000002570 interstitial cell Anatomy 0.000 claims description 2
- 201000010985 invasive ductal carcinoma Diseases 0.000 claims description 2
- 210000001117 keloid Anatomy 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 208000022013 kidney Wilms tumor Diseases 0.000 claims description 2
- 208000032839 leukemia Diseases 0.000 claims description 2
- 206010024627 liposarcoma Diseases 0.000 claims description 2
- 210000004185 liver Anatomy 0.000 claims description 2
- 201000004593 malignant giant cell tumor Diseases 0.000 claims description 2
- 201000000289 malignant teratoma Diseases 0.000 claims description 2
- 210000002418 meninge Anatomy 0.000 claims description 2
- 208000010492 mucinous cystadenocarcinoma Diseases 0.000 claims description 2
- 208000025113 myeloid leukemia Diseases 0.000 claims description 2
- 208000009091 myxoma Diseases 0.000 claims description 2
- 201000008026 nephroblastoma Diseases 0.000 claims description 2
- 210000000653 nervous system Anatomy 0.000 claims description 2
- 208000007538 neurilemmoma Diseases 0.000 claims description 2
- 201000004662 neurofibroma of spinal cord Diseases 0.000 claims description 2
- 208000004649 neutrophil actin dysfunction Diseases 0.000 claims description 2
- 208000003388 osteoid osteoma Diseases 0.000 claims description 2
- 208000008798 osteoma Diseases 0.000 claims description 2
- 210000003101 oviduct Anatomy 0.000 claims description 2
- 208000021255 pancreatic insulinoma Diseases 0.000 claims description 2
- 208000024724 pineal body neoplasm Diseases 0.000 claims description 2
- 201000004123 pineal gland cancer Diseases 0.000 claims description 2
- 208000029922 reticulum cell sarcoma Diseases 0.000 claims description 2
- 201000009410 rhabdomyosarcoma Diseases 0.000 claims description 2
- 206010039667 schwannoma Diseases 0.000 claims description 2
- 208000004548 serous cystadenocarcinoma Diseases 0.000 claims description 2
- 210000003625 skull Anatomy 0.000 claims description 2
- 210000002784 stomach Anatomy 0.000 claims description 2
- 208000001608 teratocarcinoma Diseases 0.000 claims description 2
- 210000001550 testis Anatomy 0.000 claims description 2
- 206010044412 transitional cell carcinoma Diseases 0.000 claims description 2
- 208000022271 tubular adenoma Diseases 0.000 claims description 2
- 210000003708 urethra Anatomy 0.000 claims description 2
- 210000004291 uterus Anatomy 0.000 claims description 2
- 210000001215 vagina Anatomy 0.000 claims description 2
- 208000009540 villous adenoma Diseases 0.000 claims description 2
- 210000003905 vulva Anatomy 0.000 claims description 2
- 229940124759 SOS inhibitor Drugs 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 25
- ILPWEAHQRAWJIU-OAHLLOKOSA-N 2-methyl-3-[(1R)-1-[(4-methyl-7-morpholin-4-ylpyrido[3,4-d]pyridazin-1-yl)amino]ethyl]benzonitrile Chemical compound C[C@@H](NC1=NN=C(C)C2=CN=C(C=C12)N1CCOCC1)C1=CC=CC(C#N)=C1C ILPWEAHQRAWJIU-OAHLLOKOSA-N 0.000 description 40
- 239000003795 chemical substances by application Substances 0.000 description 31
- 102100032929 Son of sevenless homolog 1 Human genes 0.000 description 30
- 101710146001 Son of sevenless homolog 1 Proteins 0.000 description 30
- 230000001225 therapeutic effect Effects 0.000 description 28
- 102000016914 ras Proteins Human genes 0.000 description 27
- 125000000217 alkyl group Chemical group 0.000 description 25
- 241000699670 Mus sp. Species 0.000 description 22
- 125000000753 cycloalkyl group Chemical group 0.000 description 22
- 102100030708 GTPase KRas Human genes 0.000 description 20
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 20
- 229940126270 MRTX0902 Drugs 0.000 description 19
- 230000035772 mutation Effects 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 125000003118 aryl group Chemical group 0.000 description 18
- 229910052739 hydrogen Inorganic materials 0.000 description 18
- 239000001257 hydrogen Substances 0.000 description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 18
- 125000003545 alkoxy group Chemical group 0.000 description 16
- LMMJFBMMJUMSJS-UHFFFAOYSA-N CH5126766 Chemical compound CNS(=O)(=O)NC1=NC=CC(CC=2C(OC3=CC(OC=4N=CC=CN=4)=CC=C3C=2C)=O)=C1F LMMJFBMMJUMSJS-UHFFFAOYSA-N 0.000 description 15
- 108010014186 ras Proteins Proteins 0.000 description 15
- 125000001188 haloalkyl group Chemical group 0.000 description 14
- 125000001072 heteroaryl group Chemical group 0.000 description 13
- 230000002195 synergetic effect Effects 0.000 description 13
- JYGYVFGNDRRLAT-MRXNPFEDSA-N 2-methyl-3-[(1R)-1-[[4-methyl-7-(4-methylpiperazin-1-yl)pyrido[3,4-d]pyridazin-1-yl]amino]ethyl]benzonitrile Chemical compound C[C@@H](NC1=NN=C(C)C2=CN=C(C=C12)N1CCN(C)CC1)C1=CC=CC(C#N)=C1C JYGYVFGNDRRLAT-MRXNPFEDSA-N 0.000 description 12
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
- 230000001105 regulatory effect Effects 0.000 description 12
- YWEVONIJEAVHLR-MRXNPFEDSA-N 3-[(1R)-1-[[7-[3-(dimethylamino)-3-methylazetidin-1-yl]-4-methylpyrido[3,4-d]pyridazin-1-yl]amino]ethyl]-2-methylbenzonitrile Chemical compound C[C@@H](NC1=NN=C(C)C2=CN=C(C=C12)N1CC(C)(C1)N(C)C)C1=CC=CC(C#N)=C1C YWEVONIJEAVHLR-MRXNPFEDSA-N 0.000 description 11
- 125000004093 cyano group Chemical group *C#N 0.000 description 11
- RFONUTGWBGKGSZ-OAHLLOKOSA-N 2-methyl-3-[(1R)-1-[(4-methyl-7-piperazin-1-ylpyrido[3,4-d]pyridazin-1-yl)amino]ethyl]benzonitrile Chemical compound C[C@@H](NC1=NN=C(C)C2=CN=C(C=C12)N1CCNCC1)C1=CC=CC(C#N)=C1C RFONUTGWBGKGSZ-OAHLLOKOSA-N 0.000 description 10
- YUARIZVBKORWBV-QGZVFWFLSA-N 3-[(1R)-1-[[7-(4-ethylpiperazin-1-yl)-4-methylpyrido[3,4-d]pyridazin-1-yl]amino]ethyl]-2-methylbenzonitrile Chemical compound CCN1CCN(CC1)C1=NC=C2C(C)=NN=C(N[C@H](C)C3=CC=CC(C#N)=C3C)C2=C1 YUARIZVBKORWBV-QGZVFWFLSA-N 0.000 description 10
- FIDGOMNHJXAUMR-APWZRJJASA-N 3-[(1R)-1-[[7-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-4-methylpyrido[3,4-d]pyridazin-1-yl]amino]ethyl]-2-methylbenzonitrile Chemical compound C[C@@H](NC1=NN=C(C)C2=CN=C(C=C12)N1CC[C@@H](C1)N(C)C)C1=CC=CC(C#N)=C1C FIDGOMNHJXAUMR-APWZRJJASA-N 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- XKMLYUALXHKNFT-UUOKFMHZSA-N Guanosine-5'-triphosphate Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XKMLYUALXHKNFT-UUOKFMHZSA-N 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- 229910052736 halogen Inorganic materials 0.000 description 9
- 150000002367 halogens Chemical group 0.000 description 9
- 125000000623 heterocyclic group Chemical group 0.000 description 9
- 238000003556 assay Methods 0.000 description 8
- 208000035475 disorder Diseases 0.000 description 8
- 108090000623 proteins and genes Proteins 0.000 description 8
- -1 -O-alkyl Chemical compound 0.000 description 7
- 230000004071 biological effect Effects 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 238000000338 in vitro Methods 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 230000037361 pathway Effects 0.000 description 7
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 6
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 6
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 6
- 102000018898 GTPase-Activating Proteins Human genes 0.000 description 6
- 108091006094 GTPase-accelerating proteins Proteins 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 102000043136 MAP kinase family Human genes 0.000 description 6
- 108091054455 MAP kinase family Proteins 0.000 description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 239000011668 ascorbic acid Substances 0.000 description 6
- 235000010323 ascorbic acid Nutrition 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 238000001356 surgical procedure Methods 0.000 description 6
- QGWNDRXFNXRZMB-UUOKFMHZSA-N GDP Chemical compound C1=2NC(N)=NC(=O)C=2N=CN1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O QGWNDRXFNXRZMB-UUOKFMHZSA-N 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- QGWNDRXFNXRZMB-UHFFFAOYSA-N guanidine diphosphate Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(COP(O)(=O)OP(O)(O)=O)C(O)C1O QGWNDRXFNXRZMB-UHFFFAOYSA-N 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 230000036515 potency Effects 0.000 description 5
- 235000018102 proteins Nutrition 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 230000011664 signaling Effects 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- JYRFUEVDZSADMW-XLIONFOSSA-N 3-[(1R)-1-[[7-[(9aS)-3,4,6,7,9,9a-hexahydro-1H-pyrazino[2,1-c][1,4]oxazin-8-yl]-4-methylpyrido[3,4-d]pyridazin-1-yl]amino]ethyl]-2-methylbenzonitrile Chemical compound [H][C@]12COCCN1CCN(C2)C1=NC=C2C(C)=NN=C(N[C@H](C)C3=CC=CC(C#N)=C3C)C2=C1 JYRFUEVDZSADMW-XLIONFOSSA-N 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- 102000013446 GTP Phosphohydrolases Human genes 0.000 description 4
- 101000868154 Homo sapiens Son of sevenless homolog 2 Proteins 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 241000124008 Mammalia Species 0.000 description 4
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 4
- 108700020796 Oncogene Proteins 0.000 description 4
- 102100032930 Son of sevenless homolog 2 Human genes 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 230000004913 activation Effects 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
- 150000001413 amino acids Chemical group 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- ACWZRVQXLIRSDF-UHFFFAOYSA-N binimetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1F ACWZRVQXLIRSDF-UHFFFAOYSA-N 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 230000001413 cellular effect Effects 0.000 description 4
- 229940127089 cytotoxic agent Drugs 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000003993 interaction Effects 0.000 description 4
- 229940043355 kinase inhibitor Drugs 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- 239000002773 nucleotide Substances 0.000 description 4
- 125000003729 nucleotide group Chemical group 0.000 description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 4
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 4
- 239000000523 sample Substances 0.000 description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 3
- JLOXTZFYJNCPIS-FYWRMAATSA-N (z)-3-amino-3-(4-aminophenyl)sulfanyl-2-[2-(trifluoromethyl)phenyl]prop-2-enenitrile Chemical compound C=1C=CC=C(C(F)(F)F)C=1C(\C#N)=C(/N)SC1=CC=C(N)C=C1 JLOXTZFYJNCPIS-FYWRMAATSA-N 0.000 description 3
- TUSDEZXZIZRFGC-UHFFFAOYSA-N 1-O-galloyl-3,6-(R)-HHDP-beta-D-glucose Natural products OC1C(O2)COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC1C(O)C2OC(=O)C1=CC(O)=C(O)C(O)=C1 TUSDEZXZIZRFGC-UHFFFAOYSA-N 0.000 description 3
- PYHXGXCGESYPCW-UHFFFAOYSA-M 2,2-diphenylacetate Chemical compound C=1C=CC=CC=1C(C(=O)[O-])C1=CC=CC=C1 PYHXGXCGESYPCW-UHFFFAOYSA-M 0.000 description 3
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 3
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 3
- 239000005711 Benzoic acid Substances 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 108020004705 Codon Proteins 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000001263 FEMA 3042 Substances 0.000 description 3
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 3
- 229940124785 KRAS inhibitor Drugs 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 description 3
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 229920002230 Pectic acid Polymers 0.000 description 3
- LRBQNJMCXXYXIU-PPKXGCFTSA-N Penta-digallate-beta-D-glucose Natural products OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@@H]2[C@H]([C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-PPKXGCFTSA-N 0.000 description 3
- 108010020346 Polyglutamic Acid Proteins 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 235000011054 acetic acid Nutrition 0.000 description 3
- 230000000996 additive effect Effects 0.000 description 3
- 239000000783 alginic acid Substances 0.000 description 3
- 235000010443 alginic acid Nutrition 0.000 description 3
- 229960001126 alginic acid Drugs 0.000 description 3
- 229920000615 alginic acid Polymers 0.000 description 3
- 150000004781 alginic acids Chemical class 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 230000003281 allosteric effect Effects 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 3
- 229940072107 ascorbate Drugs 0.000 description 3
- 229960005070 ascorbic acid Drugs 0.000 description 3
- 229940050390 benzoate Drugs 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 3
- 150000007942 carboxylates Chemical class 0.000 description 3
- WBYWAXJHAXSJNI-UHFFFAOYSA-N cinnamic acid Chemical compound OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 3
- 229940001468 citrate Drugs 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000002255 enzymatic effect Effects 0.000 description 3
- LRBQNJMCXXYXIU-QWKBTXIPSA-N gallotannic acid Chemical compound OC1=C(O)C(O)=CC(C(=O)OC=2C(=C(O)C=C(C=2)C(=O)OC[C@H]2[C@@H]([C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)[C@@H](OC(=O)C=3C=C(OC(=O)C=4C=C(O)C(O)=C(O)C=4)C(O)=C(O)C=3)O2)OC(=O)C=2C=C(OC(=O)C=3C=C(O)C(O)=C(O)C=3)C(O)=C(O)C=2)O)=C1 LRBQNJMCXXYXIU-QWKBTXIPSA-N 0.000 description 3
- 229940093915 gynecological organic acid Drugs 0.000 description 3
- 125000005549 heteroarylene group Chemical group 0.000 description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 3
- 238000002955 isolation Methods 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 229940049920 malate Drugs 0.000 description 3
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 3
- 239000001630 malic acid Substances 0.000 description 3
- 235000011090 malic acid Nutrition 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 3
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 3
- 229910017604 nitric acid Inorganic materials 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 235000005985 organic acids Nutrition 0.000 description 3
- 235000006408 oxalic acid Nutrition 0.000 description 3
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- 239000010318 polygalacturonic acid Substances 0.000 description 3
- 229920002643 polyglutamic acid Polymers 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 3
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 3
- 235000015523 tannic acid Nutrition 0.000 description 3
- 229940033123 tannic acid Drugs 0.000 description 3
- 229920002258 tannic acid Polymers 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- 231100001274 therapeutic index Toxicity 0.000 description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 3
- 238000011144 upstream manufacturing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QFWCYNPOPKQOKV-UHFFFAOYSA-N 2-(2-amino-3-methoxyphenyl)chromen-4-one Chemical compound COC1=CC=CC(C=2OC3=CC=CC=C3C(=O)C=2)=C1N QFWCYNPOPKQOKV-UHFFFAOYSA-N 0.000 description 2
- RCLQNICOARASSR-SECBINFHSA-N 3-[(2r)-2,3-dihydroxypropyl]-6-fluoro-5-(2-fluoro-4-iodoanilino)-8-methylpyrido[2,3-d]pyrimidine-4,7-dione Chemical compound FC=1C(=O)N(C)C=2N=CN(C[C@@H](O)CO)C(=O)C=2C=1NC1=CC=C(I)C=C1F RCLQNICOARASSR-SECBINFHSA-N 0.000 description 2
- WGPXKFOFEXJMBD-UHFFFAOYSA-N 3-[N-[3-[(dimethylamino)methyl]phenyl]-C-phenylcarbonimidoyl]-2-hydroxy-1H-indole-6-carboxamide Chemical compound CN(C)CC1=CC(=CC=C1)N=C(C2=CC=CC=C2)C3=C(NC4=C3C=CC(=C4)C(=O)N)O WGPXKFOFEXJMBD-UHFFFAOYSA-N 0.000 description 2
- VJNZMSLGVUSPCF-UHFFFAOYSA-N 5-bromo-2-(2-chloro-4-iodoanilino)-n-(cyclopropylmethoxy)-3,4-difluorobenzamide Chemical compound C1CC1CONC(=O)C=1C=C(Br)C(F)=C(F)C=1NC1=CC=C(I)C=C1Cl VJNZMSLGVUSPCF-UHFFFAOYSA-N 0.000 description 2
- XXSSGBYXSKOLAM-UHFFFAOYSA-N 5-bromo-n-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide Chemical compound OCC(O)CONC(=O)C1=CC(Br)=C(F)C(F)=C1NC1=CC=C(I)C=C1F XXSSGBYXSKOLAM-UHFFFAOYSA-N 0.000 description 2
- PEKZLFZZBGBOPJ-UHFFFAOYSA-N COC=1C=C2C(=NC=NC2=CC=1OC)NC1=C(C=C(C=C1)OC1=CC=CC=C1)C Chemical compound COC=1C=C2C(=NC=NC2=CC=1OC)NC1=C(C=C(C=C1)OC1=CC=CC=C1)C PEKZLFZZBGBOPJ-UHFFFAOYSA-N 0.000 description 2
- 101100421901 Caenorhabditis elegans sos-1 gene Proteins 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- ZEZHPEIEEFTILY-QMMMGPOBSA-N G-573 Chemical compound C[C@H](O)CONC(=O)C=1OC2=C(F)C=NC=C2C=1NC1=CC=C(I)C=C1F ZEZHPEIEEFTILY-QMMMGPOBSA-N 0.000 description 2
- 108010026288 GTP Phosphohydrolases Proteins 0.000 description 2
- 102100039788 GTPase NRas Human genes 0.000 description 2
- 101710204378 GTPase NRas Proteins 0.000 description 2
- 108091006109 GTPases Proteins 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 102100033067 Growth factor receptor-bound protein 2 Human genes 0.000 description 2
- 108091009389 Growth factor receptor-bound protein 2 Proteins 0.000 description 2
- VIUAUNHCRHHYNE-JTQLQIEISA-N N-[(2S)-2,3-dihydroxypropyl]-3-(2-fluoro-4-iodoanilino)-4-pyridinecarboxamide Chemical compound OC[C@@H](O)CNC(=O)C1=CC=NC=C1NC1=CC=C(I)C=C1F VIUAUNHCRHHYNE-JTQLQIEISA-N 0.000 description 2
- 102000007530 Neurofibromin 1 Human genes 0.000 description 2
- 108010085793 Neurofibromin 1 Proteins 0.000 description 2
- 102000043276 Oncogene Human genes 0.000 description 2
- 206010033128 Ovarian cancer Diseases 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 241000282320 Panthera leo Species 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 102000005588 Son of Sevenless Proteins Human genes 0.000 description 2
- 108010059447 Son of Sevenless Proteins Proteins 0.000 description 2
- 102100033019 Tyrosine-protein phosphatase non-receptor type 11 Human genes 0.000 description 2
- 101150049278 US20 gene Proteins 0.000 description 2
- 101150114976 US21 gene Proteins 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 238000001574 biopsy Methods 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 208000019065 cervical carcinoma Diseases 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000012069 chiral reagent Substances 0.000 description 2
- 238000011260 co-administration Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 230000001351 cycling effect Effects 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 230000007783 downstream signaling Effects 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 230000001976 improved effect Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 230000000670 limiting effect Effects 0.000 description 2
- 201000005249 lung adenocarcinoma Diseases 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000013178 mathematical model Methods 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- DXASQZJWWGZNSF-UHFFFAOYSA-N n,n-dimethylmethanamine;sulfur trioxide Chemical group CN(C)C.O=S(=O)=O DXASQZJWWGZNSF-UHFFFAOYSA-N 0.000 description 2
- RDSACQWTXKSHJT-NSHDSACASA-N n-[3,4-difluoro-2-(2-fluoro-4-iodoanilino)-6-methoxyphenyl]-1-[(2s)-2,3-dihydroxypropyl]cyclopropane-1-sulfonamide Chemical compound C1CC1(C[C@H](O)CO)S(=O)(=O)NC=1C(OC)=CC(F)=C(F)C=1NC1=CC=C(I)C=C1F RDSACQWTXKSHJT-NSHDSACASA-N 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 101150087683 rasgrp1 gene Proteins 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- CYOHGALHFOKKQC-UHFFFAOYSA-N selumetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1Cl CYOHGALHFOKKQC-UHFFFAOYSA-N 0.000 description 2
- 230000019491 signal transduction Effects 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- JYCVYKFEUFLQCE-JTFWXBGUSA-N (2E,3E)-2-[amino-(2-aminophenyl)sulfanylmethylidene]-3-[amino-(3-aminophenyl)sulfanylmethylidene]butanedinitrile Chemical compound N/C(\SC1=CC(N)=CC=C1)=C(/C(\C#N)=C(/N)\SC(C=CC=C1)=C1N)\C#N JYCVYKFEUFLQCE-JTFWXBGUSA-N 0.000 description 1
- MEPDJWRMAAUPBM-VGUPLNMOSA-N (2s,3s)-2-[(4r)-4-[4-[(2r)-2,3-dihydroxypropoxy]phenyl]-2,5-dioxoimidazolidin-1-yl]-n-(2-fluoro-4-iodophenyl)-3-phenylbutanamide Chemical compound C1([C@H]2NC(=O)N(C2=O)[C@@H]([C@@H](C)C=2C=CC=CC=2)C(=O)NC=2C(=CC(I)=CC=2)F)=CC=C(OC[C@H](O)CO)C=C1 MEPDJWRMAAUPBM-VGUPLNMOSA-N 0.000 description 1
- RWEVIPRMPFNTLO-UHFFFAOYSA-N 2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-3-pyridinecarboxamide Chemical compound CN1C(=O)C(C)=CC(C(=O)NOCCO)=C1NC1=CC=C(I)C=C1F RWEVIPRMPFNTLO-UHFFFAOYSA-N 0.000 description 1
- FIMYFEGKMOCQKT-UHFFFAOYSA-N 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-n-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide Chemical compound FC=1C(F)=C(NC=2C(=CC(I)=CC=2)F)C(C(=O)NOCCO)=CC=1CN1OCCCC1=O FIMYFEGKMOCQKT-UHFFFAOYSA-N 0.000 description 1
- ZGXOBLVQIVXKEB-UHFFFAOYSA-N 3-[N-[3-[(dimethylamino)methyl]phenyl]-C-phenylcarbonimidoyl]-2-hydroxy-N,N-dimethyl-1H-indole-6-carboxamide Chemical compound CN(C)CC1=CC(=CC=C1)N=C(C2=CC=CC=C2)C3=C(NC4=C3C=CC(=C4)C(=O)N(C)C)O ZGXOBLVQIVXKEB-UHFFFAOYSA-N 0.000 description 1
- NLHHRLWOUZZQLW-UHFFFAOYSA-N Acrylonitrile Chemical compound C=CC#N NLHHRLWOUZZQLW-UHFFFAOYSA-N 0.000 description 1
- 108700028369 Alleles Proteins 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000005623 Carcinogenesis Diseases 0.000 description 1
- 108010001857 Cell Surface Receptors Proteins 0.000 description 1
- 206010008263 Cervical dysplasia Diseases 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 101100412663 Danio rerio rasgef1bb gene Proteins 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 206010014733 Endometrial cancer Diseases 0.000 description 1
- 206010014759 Endometrial neoplasm Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 208000000461 Esophageal Neoplasms Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 238000012413 Fluorescence activated cell sorting analysis Methods 0.000 description 1
- RFWVETIZUQEJEF-UHFFFAOYSA-N GDC-0623 Chemical compound OCCONC(=O)C=1C=CC2=CN=CN2C=1NC1=CC=C(I)C=C1F RFWVETIZUQEJEF-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000016285 Guanine Nucleotide Exchange Factors Human genes 0.000 description 1
- 108010067218 Guanine Nucleotide Exchange Factors Proteins 0.000 description 1
- 241000713858 Harvey murine sarcoma virus Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101100477990 Homo sapiens SOS1 gene Proteins 0.000 description 1
- 101001087416 Homo sapiens Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 206010069755 K-ras gene mutation Diseases 0.000 description 1
- 206010061523 Lip and/or oral cavity cancer Diseases 0.000 description 1
- 108060006687 MAP kinase kinase kinase Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 101100477993 Mus musculus Sos2 gene Proteins 0.000 description 1
- SUDAHWBOROXANE-UHFFFAOYSA-N N-(2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide Chemical compound OCC(O)CONC(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F SUDAHWBOROXANE-UHFFFAOYSA-N 0.000 description 1
- BINUSKKWHKURHD-UHFFFAOYSA-N N-(cyclopropylmethoxy)-3,4,5-trifluoro-2-[(4-iodo-2-methylphenyl)methyl]benzamide Chemical compound CC1=C(CC(C(F)=C(C(F)=C2)F)=C2C(NOCC2CC2)=O)C=CC(I)=C1 BINUSKKWHKURHD-UHFFFAOYSA-N 0.000 description 1
- 206010029748 Noonan syndrome Diseases 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 108020004711 Nucleic Acid Probes Proteins 0.000 description 1
- MMJRAJHHBNKVOK-UHFFFAOYSA-N O=C(C(C=C1)=C(CC(C=CC(I)=C2)=C2Cl)C(F)=C1F)NOCC1CC1 Chemical compound O=C(C(C=C1)=C(CC(C=CC(I)=C2)=C2Cl)C(F)=C1F)NOCC1CC1 MMJRAJHHBNKVOK-UHFFFAOYSA-N 0.000 description 1
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 238000011579 SCID mouse model Methods 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 241000282898 Sus scrofa Species 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 208000024770 Thyroid neoplasm Diseases 0.000 description 1
- 101710116241 Tyrosine-protein phosphatase non-receptor type 11 Proteins 0.000 description 1
- BSMCAPRUBJMWDF-UHFFFAOYSA-N [3,4-difluoro-2-(2-fluoro-4-iodoanilino)phenyl]-(3-hydroxy-3-piperidin-2-ylazetidin-1-yl)methanone Chemical compound C1C(O)(C2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F BSMCAPRUBJMWDF-UHFFFAOYSA-N 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001668 ameliorated effect Effects 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000003140 astrocytic effect Effects 0.000 description 1
- METKIMKYRPQLGS-UHFFFAOYSA-N atenolol Chemical compound CC(C)NCC(O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 229950003054 binimetinib Drugs 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000036952 cancer formation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 229960002271 cobimetinib Drugs 0.000 description 1
- RESIMIUSNACMNW-BXRWSSRYSA-N cobimetinib fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F RESIMIUSNACMNW-BXRWSSRYSA-N 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000006552 constitutive activation Effects 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 230000037437 driver mutation Effects 0.000 description 1
- 230000008406 drug-drug interaction Effects 0.000 description 1
- 201000003914 endometrial carcinoma Diseases 0.000 description 1
- 201000004101 esophageal cancer Diseases 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000000799 fluorescence microscopy Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 238000003205 genotyping method Methods 0.000 description 1
- 201000006604 granular cell tumor Diseases 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 102000009543 guanyl-nucleotide exchange factor activity proteins Human genes 0.000 description 1
- 108040001860 guanyl-nucleotide exchange factor activity proteins Proteins 0.000 description 1
- 201000003911 head and neck carcinoma Diseases 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 230000037417 hyperactivation Effects 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 201000005264 laryngeal carcinoma Diseases 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 208000012987 lip and oral cavity carcinoma Diseases 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 201000005296 lung carcinoma Diseases 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 102000006240 membrane receptors Human genes 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 208000025189 neoplasm of testis Diseases 0.000 description 1
- 238000007481 next generation sequencing Methods 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002853 nucleic acid probe Substances 0.000 description 1
- 210000004940 nucleus Anatomy 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 230000004650 oncogenic pathway Effects 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229950002592 pimasertib Drugs 0.000 description 1
- 238000003752 polymerase chain reaction Methods 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 201000001514 prostate carcinoma Diseases 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 108700042226 ras Genes Proteins 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229950008933 refametinib Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 238000003757 reverse transcription PCR Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229950010746 selumetinib Drugs 0.000 description 1
- 210000000717 sertoli cell Anatomy 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 102000030938 small GTPase Human genes 0.000 description 1
- 108060007624 small GTPase Proteins 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 230000002381 testicular Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000759 toxicological effect Toxicity 0.000 description 1
- 229960004066 trametinib Drugs 0.000 description 1
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 1
- 230000002463 transducing effect Effects 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to combination therapies useful for treating cancer.
- the present invention relates to therapeutically effective combinations of a Son of sevenless homolog 1 (SOS1) inhibitor and a KRas G12C inhibitor, pharmaceutical compositions comprising the inhibitors, kits comprising the compositions and methods of use therefor.
- SOS1 Son of sevenless homolog 1
- KRas G12C inhibitor KRas G12C inhibitor
- KRas Kirsten Rat Sarcoma 2 Viral Oncogene Homolog
- GDP -bound inactive
- GTP -bound active
- cellular proliferation e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401.
- KRas The role of activated KRas in malignancy was observed over thirty years ago (e.g., see Der et al., (1982) Proc. Natl Acad. Sci. USA 79(11):3637-3640).
- Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25 - 30% of lung adenocarcinomas, (e.g., see Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928-942 doi: 10.1038/nrd428).
- Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma, with a G12C transversion being the most common activating mutation (e.g., see Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177, published online 2012 Sep 26. doi: 10.1158/1078-0432.CCR- 11-3265).
- KRas inhibitor has demonstrated sufficient safety and/or efficacy to obtain regulatory approval (e.g., see McCormick (2015) Clin Cancer Res. 21 (8): 1797-1801).
- KRas G12C inhibitors disclosed herein are potent inhibitors of KRas G12C enzymatic activity and exhibit single agent activity inhibiting the in vitro proliferation of cell lines harboring a KRas G12C mutation
- the relative potency and/or observed maximal effect of any given KRas G12C inhibitor can vary between KRas mutant cell lines. The reason or reasons for the range of potencies and observed maximal effect is not fully understood but certain cell lines appear to possess differing intrinsic resistance.
- the Ras family comprises v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRas), neuroblastoma RAS viral oncogene homolog (NRAS), and Harvey murine sarcoma virus oncogene (HRas) and critically regulates cellular division, growth and function in normal and altered states including cancer (see e.g., Simanshu et al. Cell, 2017. 170(1): p. 17-33; Matikas et al., Crit Rev Oncol Hematol, 2017. 110: p. 1-12).
- RAS proteins are activated by upstream signals, including receptor tyrosine kinases (RTKs), and transduce signals to several downstream signaling pathways such as the mitogen-activated protein kinase (MAPK)/extracellular signal- regulated kinases (ERK) pathway.
- RTKs receptor tyrosine kinases
- MAPK mitogen-activated protein kinase
- ERK extracellular signal- regulated kinases
- RAS proteins are guanosine triphosphatases (GTPases) that cycle between an inactive, guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate (GTP)-bound state.
- GTPases guanosine triphosphatases
- GAPs extrinsic GTPase activating proteins
- GEFs guanine echange factors
- SOS1 Son of sevenless homolog 1
- SOS1 is a GEF that mediates the exchange of GDP for GTP, thereby activating RAS proteins. This regulation through GAPs and GEFs is the mechanism whereby activation and deactivation are tightly regulated under normal conditions.
- RAS-GEF families that have been identified in mammalian cells are SOS, RAS-GRF and RAS-GRP (Rojas, 2011).
- RAS-GRF and RAS-GRP are expressed in the cells of the central nervous system and hematopoietic cells, respectively, while the SOS family is ubiquitously expressed and is responsible for transducing RTK signaling.
- the SOS family comprises SOS1 and SOS2 and these proteins share approximately 70% sequence identity.
- SOS1 appears to be much more active than SOS2 due to the rapid degradation of SOS2.
- the mouse SOS2 knockout is viable whereas the SOS1 knockout is embryonic lethal.
- a tamoxifen-inducible SOS1 knockout mouse model was used to interrogate the role of SOS1 and SOS2 in adult mice and demonstrated the SOS1 knockout was viable but the SOS 1/2 double knockout was not viable (Baltanas, 2013) suggesting functional redundancy and that selective inhibition of SOS1 may have a sufficient therapeutic index for the treatment of SOS1 - RAS activated diseases.
- SOS proteins are recruited to phosphorylated RTKs through an interaction with growth factor receptor bound protein 2 (GRB2). Recruitment to the plasma membrane places SOS in close proximity to RAS and enables SOS-mediated RAS activation. SOS proteins bind to RAS through a catalytic binding site that promotes nucleotide exchange as well as through an allosteric site that binds GTP -bound RAS-family proteins which increases the catalytic function of SOS (Freedman et al., Proc. Natl. Acad. Sci, USA 2006. 103(45): p. 16692-97).
- Binding to the allosteric site relieves steric occlusion of the catalytic site and is therefore required for full activation of the catalytic site. Retention of the active conformation at the catalytic site following interaction with the allosteric site is maintained in isolation due to strengthened interactions of key domains in the activated state.
- SOS1 mutations are found in Noonan syndrome and several cancers including lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testis tumor and granular cell tumors of the skin (see e.g., Denayer, E., et al, Genes Chromosomes Cancer, 2010. 49(3): p. 242-52).
- GTPase-activating proteins are proteins that stimulate the low intrinsic GTPase activity of RAS family members and therefore converts active GTP -bound RAS proteins into inactive, GDP-bound RAS proteins (e.g., see Simanshu, D.K., Cell, 2017, Ras Proteins and their Regulators in Human Disease). While activating alterations in the phosphatase PTPN11(SHP2) and the GEF SOS1 occur in cancers, inactivating mutations and loss-of-function alterations in the GAP neurofibromin 1 (NF-1) also occur creating a state where SO SI activity is unopposed and activity downstream of the pathway through RAS proteins is elevated.
- GAP neurofibromin 1 NF-1
- the mitogen-activated protein kinase (MAPK) signaling pathway is involved in the regulation of various cellular activities, including , but not limited to cell proliferation, survival, differentiation, and motility.
- the classical MAPK pathway consists of Ras (a family of related proteins which is expressed in all animal cell lineages and organs), Raf (a family of three serine/threonine-specific protein kinases that are related to retroviral oncogenes), MEK (mitogen-activated protein kinase kinase), and ERK (extracellular signal-regulated kinases), sequentially relaying proliferative signals generated at the cell surface receptors into the nucleus through cytoplasmic signaling.
- Ras a family of related proteins which is expressed in all animal cell lineages and organs
- Raf a family of three serine/threonine-specific protein kinases that are related to retroviral oncogenes
- MEK mitogen-activated protein kinase kinase
- MEK inhibitors target the Ras/Raf/MEK/ERK signaling pathway, thereby inhibiting cell proliferation and inducing apoptosis.
- the MAPK pathway is one of the most commonly mutated oncogenic pathways in cancer, Deregulation of this pathway is frequently observed and plays a central role in the carcinogenesis and maintenance of several cancers, including melanoma, pancreatic, lung, colorectal, and breast cancers, (e.g., Neuzillet et al., (2014) Pharmacology & Therapeutics 141:160-171).
- MEK inhibitors suitable for the provided compositions and methods include, but are not limited to selumetinib, 6-(4-bromo-2-chl oroanilino)-7-fluoro-N-(2 -hydroxy ethoxy)-3- methylbenzimidazole-5-carboxamide; AZD8330, 2-(2-fluoro-4-iodoanilino)-N-(2- hydroxyethoxy)-l,5-dimethyl-6-oxopyridine-3-carboxamide; PD0325901, N-[(2R)-2,3- dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide; PD318088, 5-bromo-N- (2,3-dihydroxypropoxy)-3,4-di
- R05126766 (VS-6766), 3-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-4-methyl- 7-pyrimidin-2-yloxychromen-2-one; WX-554, HL-085; ClnQ-03; G-573, 7-fluoro-3-(2-fluoro-4- iodoanilino)-N-[(2S)-2-hydroxypropoxy]furo[3 ,2-c]pyridine-2-carboxamide; PD 184161, 5- bromo-2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide;
- R05068760 (2S,3S)-2-[(4R)-4-[4-[(2R)-2,3-dihydroxypropoxy]phenyl]-2,5-dioxoimidazolidin- l-yl]-N-(2-fluoro-4-iodophenyl)-3-phenylbutanamide; SL327, (Z)-3 -amino-3 -(4- aminophenyl)sulfanyl-2-[2-(trifluoromethyl)phenyl]prop-2-enenitrile; MEK162 (Arry-162), 5- ((4-bromo-2-fluorophenyl)amino)-4-fluoro-N-(2-hydroxy ethoxy)- 1 -methyl- 1H- benzo[d]imidazole-6-carboxamide; Tak-733, (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-((2-fluoro- 4-iodophen
- One of the MEK inhibitors suitable for the provided compositions and methods is VS- 6766 which has the following structure:
- MEK inhibitors Methods for manufacturing MEK inhibitors, or pharmaceutically acceptable salts or pharmaceutical compositions thereof are well known to those skilled in the art and MEK inhibitors may be obtained from a wide-variety of commercial suppliers, in forms suitable for both research or human use.
- suitable MEK inhibitors for use in the compositions and methods disclosed herein and methods for preparing such inhibitors are disclosed in US Patent Application Publication Nos: 20190144382; 20180370948; 20180296533; 20180147192; 20180118715; 20170231963; 20170183348; 20170183333; 20170166523; 20170101408; 20170096388; 20160331753; 20160168103; 20160168102; 20160136150; 20160108041; 20150141399; 20150133424; 20150051209; 20140378466; 20140275527; 20140135519; 20140128442; 20140080804; 20130150573; 20130018075; 20120238599; 2019
- the combination therapy of the present invention in one aspect, synergistically increases the potency of KRas G12C inhibitors resulting in improved efficacy of KRas G12C inhibitors disclosed herein.
- the combination therapy of the present invention in another aspect, provides improved clinical benefit to patients compared to treatment with KRas G12C inhibitors disclosed herein as a single agent.
- a SOS1 inhibitor such as those described in US provisional patent applications 62/951,812, 62/975,645, 63/044,802, 62/980,790 and 63/057,563 (and corresponding U.S. and international applications and publications including PCT/US20/66003, PCT/US21/19184, PCT/US21/43309 and US 17/127,582) as described in greated detail herein, for instance:
- a SOS1 inhibitor such as BI1701963 or a pharmaceutically acceptable salt thereof
- the invention provides a therapeutically effective combination of: the SOS1 inhibitor (f?)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4- ⁇ i]pyridazin-l- yl)amino)ethyl)benzonitrile (also known as MRTX0902), having the formula:
- the invention provides a therapeutically effective combination of: the SOS1 inhibitor (f?)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4- ⁇ i]pyridazin-l- yl)amino)ethyl)benzonitrile (also known as MRTX0902), having the formula:
- compositions for use in the methods comprising a therapeutically effective amount of a combination of a SOS1 inhibitor such as (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-l- yl)amino)ethyl)benzonitrile, 3-((R)-l-((7-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(l-((7-(3- (dimethylamino)-3-methylazetidin-l-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino
- SOS1 inhibitor such as (R)-2-
- the methods may further comprise administering MEK inhibitors to the subject in need thereof, so that the subject is being administered adagrasib, a SOS1 inhibitor, and a MEK inhibitor, for example VS-6766.
- a SOS1 inhibitor such as (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4- djpyridazin- 1 -yl)amino)ethyl)benzonitrile, 3 -((R)- 1 -((7-((S)-hexahydropyrazino[2, 1 - c][l,4]oxazin-8(lH)-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2- methylbenzonitrile, (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)-4-methylpyrido[3,4
- a SOS1 inhibitor such as (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4- djpyri
- SOS1 inhibitor such as BI1701963, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the KRas G12C inhibitor adagrasib, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
- the cancer is a KRas G12C-associated cancer.
- the KRas G12C-associated cancer is lung cancer.
- KRas G12C inhibitor compounds and SOS1 inhibitors are the only active agents in the provided compositions and methods.
- SOS1 inhibitors suitable for the provided compositions and methods include, but are not limited to (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4- djpyridazin- 1 -yl)amino)ethyl)benzonitrile, 3 -((R)- 1 -((7-((S)-hexahydropyrazino[2, 1 - c][l,4]oxazin-8(lH)-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2- methylbenzonitrile, (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-y
- SOS1 inhibitors suitable for the provided compositions and methods include BI 1701963.
- the invention provides a method for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a combination of the KRas G12C inhibitor adagrasib: or a pharmaceutically acceptable salt thereof, and a SOS1 inhibitor.
- the SOS1 inhibitor has the following structure: pharmaceutically acceptable salt thereof.
- the method also comprises contacting the cell with a compound having the following structure: pharmaceutically acceptable salt thereof.
- the invention provides for methods for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor, comprising contacting the cancer cell with a therapeutically effective amount of a combination of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a SOS1 inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor.
- the contacting is in vitro. In one embodiment, the contacting is in vivo.
- the method comprises administering to a subject undergoing KRas G12C treatment with an effective amount of a combination the KRas G12C inhibitor adagrasib or a pharmaceutically acceptable salt thereof, and a SOS1 inhibitor, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor.
- the method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor comprises contacting the cancer cell with a therapeutically effective amount of a combination of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a SOS1 inhibitor having the following structure: pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
- the method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor also comprises contacting the cancer cell with a compound having the following structure:
- a KRas G12C mutation e.g., a KRas G12C-associated cancer
- a regulatory agency-approved e.g., FDA-approved, assay or kit
- kits comprising a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. Also provided is a kit comprising a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, for use in treating a KRas G12C cancer.
- the invention provides a kit containing a dose of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof in an amount effective to inhibit proliferation of cancer cells in a subject.
- the kit in some cases includes an insert with instructions for administration of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
- the insert may provide a user with one set of instructions for using the a SOS1 inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof in combination with the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
- the patient before treatment with the compositions or methods of the invention, the patient was treated with one or more of a chemotherapy, a targeted anticancer agent, radiation therapy, and surgery, and optionally, the prior treatment was unsuccessful; and/or the patient has been administered surgery and optionally, the surgery was unsuccessful; and/or the patient has been treated with a platinum- based chemotherapeutic agent, and optionally, the patient has been previously determined to be non-responsive to treatment with the platinum-based chemotherapeutic agent; and/or the patient has been treated with a kinase inhibitor, and optionally, the prior treatment with the kinase inhibitor was unsuccessful; and/or the patient was treated with one or more other therapeutic agent(s).
- Fig. 1 is a chart of tumor growth inhibition of MIA PaCA-2 tumor bearing mice by MRTX0902, adagrasib, and a combination of MRTX0902 and adagrasib.
- Fig. 2 is a chart of tumor growth inhibition of MIA PaCA-2 tumor bearing mice by MRTX0902, adagrasib, and a combination of MRTX0902 and adagrasib.
- Fig. 3 is a chart of tumor growth inhibition of MIA PaCA-2 tumor bearing mice by MRTX2006, adagrasib, and a combination of MRTX0902 and adagrasib.
- Fig. 4 is a chart of tumor growth inhibition of MIA PaCA-2 tumor bearing mice by MRTX4197, adagrasib, and a combination of MRTX0902 and adagrasib.
- Fig. 5 is a chart of tumor growth inhibition of LU99 tumor bearing mice by MRTX0902, adagrasib, and a combination of MRTX0902 and adagrasib.
- Fig. 6 is a chart of tumor growth inhibition of NC1-H2122 tumor bearing mice by MRTX0902; adagrasib; and a combination of MRTX0902 and adagrasib.
- Fig. 7 is a chart of tumor growth inhibition of NC1-H2122 tumor bearing mice by MRTX0902, adagrasib, a combination of MRTX0902 and VS-6766; and a combination of VS- 6766 and adagrasib.
- Fig. 8 is a chart of tumor growth inhibition of CR6256 tumor bearing mice by MRTX0902; adagrasib; and a combination of MRTX0902 and adagrasib.
- Fig. 9 is a bar chart demonstrating efficacy of a combination of MRTX849 and MRTX0902 in a variety of human tumor xenograft KRas G12C models.
- the present invention relates to combination therapies for treating KRas G12C cancers.
- the present invention relates to methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a SOS1 inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, pharmaceutical compositions comprising therapeutically effective amounts of the inhibitors, kits comprising the compositions and methods of use therefor.
- KRas G12C refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12.
- the assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variant p.Glyl2Cys.
- KRas G12C inhibitor refers to compounds of the present invention that are represented by Formula (I), Formula I-A and Formula I-B as described in WO2019099524), or pharmaceutically acceptable salts thereof (e.g., Example Nos 234, 359, 478 or 507, or a pharmaceutically acceptable salt thereof). These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12C.
- KRas G12C inhibitors of the present invention interact with and irreversibly bind to KRas G12C by forming a covalent adduct with the sulfhydryl side chain of the cysteine residue at position 12 resulting in the inhibition of the enzymatic activity of KRas G12C.
- Adagrasib is an example of a KRas G12C inhibitor
- KRas G12C-associated disease or disorder refers to diseases or disorders associated with or mediated by or having a KRas G12C mutation.
- a non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.
- SOS1 refers to the Son of sevenless homolog 1 protein encoded by the SOS1 gene that is involved in signaling through RAS pathways.
- a “SOS1 inhibitor” refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the interaction between KRAS and SOS1.
- the term “subject,” “individual, ” or “patient, ” used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans.
- the patient is a human.
- the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented.
- the subject has been identified or diagnosed as having a cancer having a KRas G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
- the subject has a tumor that is positive for a KRas G12C mutation (e.g., as determined using a regulatory agency-approved assay or kit).
- the subject can be a subject with a tumor(s) that is positive for a KRas G12C mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit).
- the subject can be a subject whose tumors have a KRas G12C mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay).
- the subject is suspected of having a KRas G12C gene-associated cancer.
- the subject has a clinical record indicating that the subject has a tumor that has a KRas G12C mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
- the term “pediatric patient” as used herein refers to a patient under the age of 16 years at the time of diagnosis or treatment.
- the term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)).
- Berhman RE Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.
- an assay is used to determine whether the patient has KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample such as a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRas G12C-associated cancer, a patient having one or more symptoms of a KRas G12C-associated cancer, and/or a patient that has an increased risk of developing a KRas G12C-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR, quantitative real-time RT-PCR, allele-specific genotyping or ddPCR). As is well-known in the art, the assays are typically performed, e.
- a sample e.g., a biological sample or a
- regulatory agency is a country’s agency for the approval of the medical use of pharmaceutical agents with the country.
- regulatory agency is the U.S. Food and Drug Administration (FDA).
- an effective amount of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of the desired target, i.e., SOS1 or KRas G12C.
- Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
- a "therapeutically effective amount" of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of SOS1 or KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
- a "therapeutically effective amount of a combination" of two compounds is an amount that together synergistically increases the activity of the combination in comparison to the therapeutically effective amount of each compound in the combination, i.e., more than merely additive.
- the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in an increased duration of overall survival (“OS”) in subjects relative to treatment with only the KRas G12C inhibitor.
- OS overall survival
- the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in an increased duration of progression-free survival (“PFS”) in subjects relative to treatment with only the KRas G12C inhibitor.
- PFS progression-free survival
- the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in increased tumor regression in subjects relative to treatment with only the KRas G12C inhibitor.
- the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in increased tumor growth inhibition in subjects relative to treatment with only the KRas G12C inhibitor.
- the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in an improvement in the duration of stable disease in subjects compared to treatment with only the KRas G12C inhibitor.
- each compound in the combination may be the same or different than the therapeutically effective amount of each compound when administered alone as a monotherapy as long as the combination is synergistic. Such amounts may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
- treatment means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.
- amelioration of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
- the term “about” when used to modify a numerically defined parameter means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg/kg may vary between 4.5 mg/kg and 5.5 mg/kg. “About” when used at the beginning of a listing of parameters is meant to modify each parameter. For example, about 0.5 mg, 0.75 mg or 1.0 mg means about 0.5 mg, about 0.75 mg or about 1.0 mg. Likewise, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, and about 25% or more.
- kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
- the KRas G12C inhibitor is:
- the KRas G12C inhibitors used in the methods of the present invention may have one or more chiral center and may be synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space.
- the compounds may be used as mixtures or the individual components/isomers may be separated using commercially available reagents and conventional methods for isolation of stereoisomers and enantiomers well-known to those skilled in the art, e.g., using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatographic HPLC columns according to the manufacturer’s instructions.
- compounds of the present invention may be synthesized using optically pure, chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Unless otherwise indicated, whenever the specification, including the claims, refers to compounds of the invention, the term “compound” is to be understood to encompass all chiral (enantiomeric and diastereomeric) and racemic forms.
- the KRas G12C inhibitor compound adagrasib used in the methods include salts of the above compounds, for instance salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid, and salts formed from quaternary ammoniums of the formula — NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate,
- inorganic acids such
- the SOS1 inhibitor is a compound selected from (R)-2-methyl-3-(l- ((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile, 3-((R)-l-((7- ((S)-hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(lH)-yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 - yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)- 4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(l-(
- the SOS1 inhibitor is BI1701963.
- the SOS1 inhibitor is a compound of the formula:
- R 1 is hydrogen, hydroxyl, Cl - C6 alkyl, alkoxy, -N(R 6 ) 2 , -NR 6 C(0)R 6 , -C(0)N(R 6 ) 2 , -SChalkyl, -S0 2 NR 6 alkyl, cycloalkyl, -Q- heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are each optionally substituted with one or more R 2 ; each Q is independently a bond, O, or NR 6 ; X is N or CR 7 ; each R 2 is independently hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, -N(R 6 ) 2 , -SCtealkyl, -NR 6 C(0)C1 - C3 alkyl, -C(0)
- the SOS1 inhibitor is a compound of the formula:
- R 1 is hydrogen, hydroxy, Cl - C6 alkyl, alkoxy, -N(R 6 )2, -NR 6 C(0)R 6 , -C(0)N(R 6 )2, -SChalkyl, -S02NR 6 alkyl, cycloalkyl, -Q- heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are each optionally substituted with one or more R 2 ; each Q is independently a bond or O; X is N or CR 7 ; each R 2 is independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, - N(R 6 )2, -SCtealkyl, -NR 6 C(0)R 6 Cl - C3 alkyl, haloalkyl, cycloalkyl or aryl; R 3 is hydrogen, hal
- the SOS1 inhibitor is a compound of the formula: or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen, hydroxyl, Cl - C6 alkyl, alkoxy, -N(R 6 ) 2 , -NR 6 C(0)R 6 , -C(0)N(R 6 ) 2 , -SChalkyl, -S0 2 NR 6 alkyl, cycloalkyl, -Q- heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl are each optionally substituted with one or more R 2 ; each Q is independently a bond,
- X is N or CR 7 ; with the proviso that when X is N, R 1 is not hydroxyl; each R 2 is independently hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, -N(R 6 ) 2 , -SCtealkyl, - NR 6 C(0)C1 - C3 alkyl, -C(0)cycloalkyl, -C(0)heretocyclyl or aryl, wherein the cycloalkyl, the heterocyclyl or the aryl are each optionally substituted with one or more R 9 ; R 3 is hydrogen, Cl - C3 alkyl, Cl - C3 haloalkyl, or cycloalkyl; Y is a bond or heteroarylene; R 4 is aryl or heteroaryl, each optionally substituted with one or more R 5 ; each R 5 is independently hydroxy, halogen, cyano, hydroxyalkyl
- the SOS1 inhibitor is a compound selected from:
- the SOS1 inhibitors used in the methods of the present invention may have one or more chiral center and may be synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space.
- the compounds may be used as mixtures or the individual components/isomers may be separated using commercially available reagents and conventional methods for isolation of stereoisomers and enantiomers well-known to those skilled in the art, e.g., using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatographic HPLC columns according to the manufacturer’s instructions.
- compounds of the present invention may be synthesized using optically pure, chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Unless otherwise indicated, whenever the specification, including the claims, refers to compounds of the invention, the term “compound” is to be understood to encompass all chiral (enantiomeric and diastereomeric) and racemic forms.
- the SOS1 inhibitor compound includes its salts, for instance salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid, and salts formed from quaternary ammoniums of the formula — NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate
- inorganic acids such
- SOS1 inhibitors and the KRas G12C compound adagrasib or pharmaceutically acceptable salts thereof may be formulated into pharmaceutical compositions.
- the invention provides pharmaceutical compositions comprising a SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, and the KRas G12C inhibitor adagrasib, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or diluent that may be used in the methods disclosed herein.
- the SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, and KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof may be independently formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal.
- SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, and KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof are administered intravenously in a hospital setting. In one embodiment, administration may be by the oral route.
- compositions may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
- diluents fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
- the preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.
- the term “pharmaceutically acceptable salt” refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects.
- examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid.
- inorganic acids for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like
- organic acids such as acetic acid, oxalic acid,
- the compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula — NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methyl sulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
- R is hydrogen, alkyl, or benzyl
- Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methyl
- the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated.
- a dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg/kg, for example 0.1 to 100 mg/kg per day, and as a further example 0.5 to about 25 mg per kilogram body weight of the recipient per day.
- a typical topical dosage will range from 0.01-3% wt/wt in a suitable carrier.
- the effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
- compositions comprising a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and a KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, may be used in the methods of use described herein.
- the SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, and the KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof can be formulated into separate or individual dosage forms which can be co-administered one after the other. Another option is that if the route of administration is the same (e.g. oral) two active compounds can be formulated into a single form for co-administration, both methods of co-administration, however, being part of the same therapeutic treatment or regimen.
- compositions comprising a SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, and/or a KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, for use in the methods may be for simultaneous, separate or sequential use.
- the SOS1 inhibitor or a pharmaceutically acceptable salt thereof is administered prior to administration of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt thereof.
- the SOS1 inhibitor, or a pharmaceutically acceptable salt thereof is administered after administration of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt thereof.
- the SOS1 inhibitor, or a pharmaceutically acceptable salt thereof is administered at about the same time as administration of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt thereof.
- each inhibitor at different times and by different routes, in some cases would be advantageous.
- the components in the combination i.e. the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt thereof and the SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, need not be necessarily administered at essentially the same time or in any order.
- Oncology drugs are typically administered at the maximum tolerated dose (“MTD”), which is the highest dose of drug that does not cause unacceptable side effects.
- MTD maximum tolerated dose
- the KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at their respective MTDs.
- the KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at its MTD and the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed in an amount less than its MTD.
- the KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is dosed at an amount less than its MTD and the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD.
- the KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs.
- the administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.
- a single dose of KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered per day (i.e., in about 24 hour intervals) (i.e., QD).
- two doses of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are administered per day (i.e., BID).
- three doses of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are administered per day (i.e., TID).
- the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered QD.
- the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are administered BID.
- the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID.
- a single dose of KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily.
- SOS1 inhibitors suitable for the provided compositions and methods include those mentioned herein, for example (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4- d]pyridazin- 1 -yl)amino)ethyl)benzonitrile, 3 -((R)- 1 -((7-((S)-hexahydropyrazino[2, 1 - c][l,4]oxazin-8(lH)-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2- methylbenzonitrile, (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)-4-methylpyrido[3,4- d]pyridazin-l-yl)amino)ethyl)-2-
- kits for treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRasKRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
- the cancer is a KRas G12C-associated cancer.
- the KRas G12C-associated cancer is lung cancer.
- the invention provides a method for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a combination of the KRas G12C inhibitor adagrasib: or a pharmaceutically acceptable salt thereof, and a SOS1 inhibitor.
- the SOS1 inhibitor has the following structure: pharmaceutically acceptable salt thereof.
- the method also comprises contacting the cell with a compound having the following structure: pharmaceutically acceptable salt thereof.
- the invention provides for methods for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor, comprising contacting the cancer cell with an effective amount of a combination of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor.
- the contacting is in vitro. In one embodiment, the contacting is in vivo. In one embodiment, the method comprises administering to a subject undergoing KRas G12C treatment with an effective amount of a combination the KRas G12C inhibitor adagrasib or a pharmaceutically acceptable salt thereof, and a SOS1 inhibitor, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor.
- the method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor comprises contacting the cancer cell with a therapeutically effective amount of a combination of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a SOS1 inhibitor having the following structure: pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
- the method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor also comprises contacting the cancer cell with a compound having the following structure: salt thereof.
- the combination therapy comprises a combination of a compound having the formula:
- the SOS1 inhibitor is:
- the SOS1 inhibitor is:
- the SOS1 inhibitor is:
- the SOS1 inhibitor is:
- the SOS1 inhibitor is:
- the SOS1 inhibitor is: Me 3 ⁇ 41e
- the SOS1 inhibitor is:
- the SOS1 inhibitor is:
- the SOS1 inhibitor is BI1701963.
- the invention provides a therapeutically effective combination of: the SOS1 inhibitor (f?)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4- ⁇ i]pyridazin-l- yl)amino)ethyl)benzonitrile (also known as MRTX0902), having the formula:
- the invention provides a therapeutically effective combination of: the SOS1 inhibitor (f?)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4- ⁇ i]pyridazin-l- yl)amino)ethyl)benzonitrile (also known as MRTX0902), having the formula:
- contacting refers to the bringing together of indicated moieties in an in vitro system or an in vivo system.
- "contacting" a cancer cell includes the administration of a combination provided herein to an individual or subject, such as a human, having KRas G12C, as well as, for example, introducing a combination provided herein into a sample containing a cellular or purified preparation containing KRas G12C.
- KRas G12C By negatively modulating the activity of KRas G12C, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12C activity within the cell.
- the degree of covalent modification of KRas G12C may be monitored in vitro using well known methods, including those described in published international PCT application numbers W02017201161 and WO2019099524.
- the inhibitory activity of combination in cells may be monitored, for example, by measuring the inhibition of KRas G12C activity of the amount of phosphorylated ERK to assess the effectiveness of treatment and dosages may be adjusted accordingly by the attending medical practitioner.
- compositions and methods provided herein may be used for the treatment of a KRas G12C-associated cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor.
- the KRas G12C-associated cancer is lung cancer.
- the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in an increased duration of progression-free survival (“PFS”) in subjects relative to treatment with only the KRas G12C inhibitor.
- PFS progression-free survival
- the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in increased tumor regression in subjects relative to treatment with only the KRas G12C inhibitor.
- the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in increased tumor growth inhibition in subjects relative to treatment with only the KRas G12C inhibitor.
- the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof results in an improvement in the duration of stable disease in subjects compared to treatment with only the KRas G12C inhibitor adagrasib.
- the SOS1 inhibitor is selected from (f?)-2-methyl-3-(l-((4-methyl-7- morpholinopyrido[3,4-i/]pyridazin-l-yl)amino)ethyl)benzonitrile, 3-((/s’)- l -((7-((S)- hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(li7)-yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 - yl)amino)ethyl)-2-methylbenzonitrile, (f?)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)- 4-methylpyrido[3,4-i/]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (i?)-2
- the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is administered in combination with the KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, once disease progression has been observed for KRas G12C monotherapy, in which the combination therapy results in enhanced clinical benefit for the patient by increasing OS, PFS, tumor regression, tumor growth inhibition or the duration of stable disease in the patient.
- the KRas G12C inhibitor is a compound selected from compound Nos. 1-678 (as numbered in WO2019099524), or a pharmaceutically acceptable salt thereof (e.g., Example No. 234, 359, 478 or 507 or a pharmaceutically acceptable salt thereof).
- the SOS1 inhibitor is selected from (R)-2-methyl-3-(l-((4- methyl-7-morpholinopyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile, 3-((R)-l-((7-((S)- hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8( lH)-yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 - yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)- 4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(l-(
- the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4- d]pyridazin-l-yl)amino)ethyl)benzonitrile, or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of adagrasib and 3-((R)-l-((7-((S)-hexahydropyrazino[2,l-c][l,4]oxazin- 8(lH)-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-2-methyl-3-(l-((4-methyl-7-(4-methylpiperazin-l- yl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile, or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-3-(l-((7-(4-ethylpiperazin-l-yl)-4-methylpyrido[3,4- d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-2-methyl-3-(l-((4-methyl-7-(piperazin-l-yl)pyrido[3,4- d]pyridazin-l-yl)amino)ethyl)benzonitrile, or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of adagrasib and 3-((R)-l-((7-((S)-3-(dimethylamino)pyrrolidin-l-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of adagrasib and (i?)-3-(l-((6-fluoro-4-methyl-7-(4-methylpiperazin-l- yl)phthalazin-l-yl)amino)ethyl)-2-methylbenzonitrile, or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of adagrasib and the SOS1 inhibitor is BI1701963.
- the compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, colorectal, pancreas, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc.
- cancers that may be treated by the compositions and methods of the invention include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
- tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas.
- these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinom
- a method for treating cancer in a subject in need thereof comprising (a) determining that cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the SO SI inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor.
- a KRas G12C mutation e.g., a KRas G12C-associated cancer
- a regulatory agency-approved e.g., FDA-approved, assay or kit
- the KRas G12C inhibitor is a compound selected from compound Nos. 1-678 (as numbered in WO2019099524), or a pharmaceutically acceptable salt thereof (e.g., one of Example Nos. 234, 359, 478 or 507 or a pharmaceutically acceptable salt thereof).
- the SOS1 inhibitor is selected from: (R)-2-methyl-3-(l-((4- methyl-7-morpholinopyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile, 3-((R)-l-((7-((S)- hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8( lH)-yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 - yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)- 4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(l-
- the therapeutic combination comprises therapeutically effective amounts of (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-l- yl)amino)ethyl)benzonitrile or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of 3-((R)-l-((7-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of (R)-2-methyl-3-(l-((4-methyl-7-(4-methylpiperazin-l-yl)pyrido[3,4- d]pyridazin-l-yl)amino)ethyl)benzonitrile or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of (R)-3-(l-((7-(4-ethylpiperazin-l-yl)-4-methylpyrido[3,4-d]pyridazin-l- yl)amino)ethyl)-2-methylbenzonitrile or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of (R)-2-methyl-3-(l-((4-methyl-7-(piperazin-l-yl)pyrido[3,4-d]pyridazin-l- yl)amino)ethyl)benzonitrile or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of 3-((R)-l-((7-((S)-3-(dimethylamino)pyrrolidin-l-yl)-4-methylpyrido[3,4- d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of (i?)-3-(l-((6-fluoro-4-methyl-7-(4-methylpiperazin-l-yl)phthalazin-l- yl)amino)ethyl)-2-methylbenzonitrile or a pharmaceutically acceptable salt thereof.
- the therapeutic combination comprises therapeutically effective amounts of BI1701963.
- the KRas G12C compound adagrasib is administered as a tablet or capsule during the period of time.
- the tablet or capsule formulation of adagrasib comprises on or more of: about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg and about 2000 mg. .
- adagrasib is orally administered once a day (QD) on a daily basis during a period of time. In one embodiment adagrasib is orally administered twice a day (BID) on a daily basis during a period of time.
- QD once a day
- BID twice a day
- the SOS1 compound is orally administered in the amount of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg, about 40 mg to about 460 mg,
- the SOS1 compound is orally administered twice a day (BID) on a daily basis during a period of time.
- adagrasib is orally administered twice a day (BID) on a daily basis during a period of time.
- the combination therapy comprises oral administration of adagrasib once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg (e.g., about 10 mg to about 380 mg, about 10 mg to about 360 mg, about 10 mg to about 340 mg, about 10 mg to about 320 mg, about 10 mg to about 300 mg, about 10 mg to about 280 mg, about 10 mg to about 260 mg, about 10 mg to about 240 mg, about 10 mg to about 220 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about
- the KRas G12C inhibitor adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is orally administered once daily. In another embodiment, the KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is orally administered twice daily.
- the addition of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof synergistically increases the activity of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof against cancer or cancer cell lines expressing KRas G12C. Any method for determining whether two compounds exhibit synergy may be used for determining the synergistic effect of the combination.
- the mathematical models use data obtained from single agent values to determine the predicted additive effect of the combination which is compared to the observed effect for the combination. If the observed effect is greater than the predicted effect, the combination is deemed to be synergistic.
- the Bliss independence model compares the observed combination response (Fo) with the predicted combination response (FP), which was obtained based on the assumption that there is no effect from drug-drug interactions.
- the combination effect is declared synergistic if Yo is greater than Yp.
- “synergistic effect” as used herein refers to combination of a KRasKRas inhibitor or a pharmaceutically acceptable salt thereof, and a SOS 1 SOS 1 inhibitor or a pharmaceutically acceptable salt thereof producing an effect, for example, any of the beneficial or desired results including clinical results or endpoints as described herein, which is greater than the sum of the effect observed when a compound such as one described in compound Nos. 1-678 as numbered in WO2019099524, for instance adagrasib, and a SOS1 inhibitor or a pharmaceutically acceptable salt thereof are administered alone.
- the KRas G12C inhibitor is adagrasib (MRTX-849, Example No.
- the SOS1 inhibitor is selected from (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-l- yl)amino)ethyl)benzonitrile, 3-((R)-l-((7-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(l-((7-(3- (dimethylamino)-3-methylazetidin-l-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2- methylbenzonitrile, (R)-3-(l-((7-(3- (di
- the synergistic therapeutic combination comprises therapeutically effective amounts of (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4- d]pyridazin-l-yl)amino)ethyl)benzonitrile and adagrasib .
- the synergistic therapeutic combination comprises therapeutically effective amounts of 3-((R)-l-((7-((S)- hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8( lH)-yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 - yl)amino)ethyl)-2-methylbenzonitrile and adagrasib.
- the synergistic therapeutic combination comprises therapeutically effective amounts of (R)-3-(l-((7-(3- (dimethylamino)-3-methylazetidin-l-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2- methylbenzonitrile and adagrasib.
- the synergistic therapeutic combination comprises therapeutically effective amounts of (R)-2-methyl-3-(l-((4-methyl-7-(4- methylpiperazin-l-yl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile and adagrasib.
- the synergistic therapeutic combination comprises therapeutically effective amounts of (7?)-3-(l-((7-(4-ethylpiperazin-l-yl)-4-methylpyrido[3,4- ⁇ i]pyridazin-l- yl)amino)ethyl)-2-methylbenzonitrile, and adagrasib.
- the synergistic therapeutic combination comprises therapeutically effective amounts of (f?)-2-methyl-3-(l-((4- methyl-7-(piperazin-l-yl)pyrido[3,4-i/]pyridazin-l-yl)amino)ethyl)benzonitrile, and adagrasib.
- the synergistic therapeutic combination comprises therapeutically effective amounts of 3-((i?)-l-((7-((ri)-3-(dimethylamino)pyrrolidin-l-yl)-4-methylpyrido[3,4- ⁇ i]pyridazin- l-yl)amino)ethyl)-2-methylbenzonitrile, and adagrasib.
- the synergistic therapeutic combination comprises therapeutically effective amounts of (i?)-3-(l-((6-fluoro-4- methyl-7-(4-methylpiperazin-l-yl)phthalazin-l-yl)amino)ethyl)-2-methylbenzonitrile and adagrasib.
- the therapeutic combination comprises therapeutically effective amounts of BI 1701963 and adagrasib.
- the methods provided herein can result in a 1% to 99% (e.g., 1% to 98%, 1% to 95%, 1% to 90%, 1 to 85%, 1 to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 2% to 99%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 70%, 2% to 65%, 2% to 60%, 2% to 55%, 2% to 50%, 2% to 45%, 2% to 40%, 2% to 35%, 2% to 30%, 2% to 25%, 2% to 2% to 40%, 2% to 35%, 2%
- time of survival means the length of time between the identification or diagnosis of cancer (e.g., any of the cancers described herein) in a mammal by a medical professional and the time of death of the mammal (caused by the cancer). Methods of increasing the time of survival in a mammal having a cancer are described herein.
- any of the methods described herein can result in an increase (e.g., a 1% to 400%, 1% to 380%, 1% to 360%, 1% to 340%, 1% to 320%, 1% to 300%, 1% to 280%, 1% to 260%, 1% to 240%, 1% to 220%, 1% to 200%, 1% to 180%, 1% to 160%,
- an increase e.g., a 1% to 400%, 1% to 380%, 1% to 360%, 1% to 340%, 1% to 320%, 1% to 300%, 1% to 280%, 1% to 260%, 1% to 240%, 1% to 220%, 1% to 200%, 1% to 180%, 1% to 160%,
- the patient before treatment with the compositions or methods of the invention, was treated with one or more of a chemotherapy, a targeted anticancer agent, radiation therapy, and surgery, and optionally, the prior treatment was unsuccessful; and/or the patient has been administered surgery and optionally, the surgery was unsuccessful; and/or the patient has been treated with a platinum- based chemotherapeutic agent, and optionally, the patient has been previously determined to be non-responsive to treatment with the platinum-based chemotherapeutic agent; and/or the patient has been treated with a kinase inhibitor, and optionally, the prior treatment with the kinase inhibitor was unsuccessful; and/or the patient was treated with one or more other therapeutic agent(s).
- the present invention also relates to a kit comprising a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. Also provided is a kit comprising a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, for use in treating a hematological cancer.
- the invention provides a kit containing a dose of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and dose of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, in an amount effective to inhibit proliferation of cancer cells, particularly KRas G12C-expressing cancer cells, in a subject.
- the kit in some cases includes an insert with instructions for administration of the a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof,.
- the insert may provide a user with one set of instructions for using the a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, in combination with the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
- mice are inoculated in the right hind flank with cells or patient derived tumor samples harboring a KRas G12C mutation.
- tumor volumes reach between 200 - 400 mm 3 in size
- the mice are divided into four groups of 4-12 mice each.
- the first group is administered vehicle only.
- the second group is administered a single agent dose of the KRas G12C inhibitor at a concentration that yields a maximal biological effect or a less than maximal biological effect, depending on the cell line and the single agent activity, that does not result in complete tumor regression.
- the third group is administered a single agent dose of the SOS1 inhibitor at a concentration that yields a maximal biological effect or a less than maximal biological effect, depending on the cell line and the single agent activity, that also does not result in complete tumor regression.
- An optional group is administered with a single agent dose of the MEK inhibitor (VS-6766) that yields less than maximal biological effect.
- the final group is administered the single agent dose of the KRas G12C inhibitor in combination with the single agent dose of the SO SI inhibitor or with single agent dose of the KRas G12C inhibitor in combination with the single agent dose of the SOS1 inhibitor and the single agent VS-6766.
- the treatment period varies from cell line to cell line but typically is between 20-42 days.
- Tumor volumes are measured using a caliper every two - three days and tumor volumes are calculated by the formula: 0.5 x (Length x Width) 2 .
- a greater degree of tumor growth inhibition for the combination in this model demonstrates that the combination therapy is likely to have a clinically meaningful benefit to treated subjects relative to treatment with only a KRas G12C inhibitor.
- mice 16 - 32 nude/nude, Balb/c nude, or NOD/SCID mice per study were inoculated in the right hind limb with 5 x 10 6 of the indicated cell line or tumor fragment. When tumor volume reached -200 - 400 mm 3 (Study Day 0), 4 or more mice in each of the four to six groups were administered p.o.
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The present invention relates to combination therapies for treating KRas G12C cancers. In particular, the present invention relates to methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a SOS1 inhibitor and a KRas G12C inhibitor, pharmaceutical compositions comprising a such compositions, kits comprising such compositions and methods of use therefor.
Description
COMBINATION THERAPIES
FIELD OF THE INVENTION
[001] The present invention relates to combination therapies useful for treating cancer. In particular, the present invention relates to therapeutically effective combinations of a Son of sevenless homolog 1 (SOS1) inhibitor and a KRas G12C inhibitor, pharmaceutical compositions comprising the inhibitors, kits comprising the compositions and methods of use therefor.
BACKGROUND OF THE INVENTION
KRas Inhibitors
[002] Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (“KRas”) is a small GTPase and a member of the Ras family of oncogenes. KRas serves as a molecular switch cycling between inactive (GDP -bound) and active (GTP -bound) states to transduce upstream cellular signals received from multiple tyrosine kinases to downstream effectors regulating a wide variety of processes, including cellular proliferation (e.g., see Alamgeer et al., (2013) Current Opin Pharmcol. 13:394-401).
[003] The role of activated KRas in malignancy was observed over thirty years ago (e.g., see Der et al., (1982) Proc. Natl Acad. Sci. USA 79(11):3637-3640). Aberrant expression of KRas accounts for up to 20% of all cancers and oncogenic KRas mutations that stabilize GTP binding and lead to constitutive activation of KRas and downstream signaling have been reported in 25 - 30% of lung adenocarcinomas, (e.g., see Samatar and Poulikakos (2014) Nat Rev Drug Disc 13(12): 928-942 doi: 10.1038/nrd428). Single nucleotide substitutions that result in missense mutations at codons 12 and 13 of the KRas primary amino acid sequence comprise approximately 40% of these KRas driver mutations in lung adenocarcinoma, with a G12C transversion being the most common activating mutation (e.g., see Dogan et al., (2012) Clin Cancer Res. 18(22):6169-6177, published online 2012 Sep 26. doi: 10.1158/1078-0432.CCR- 11-3265).
[004] The well-known role of KRas in malignancy and the discovery of these frequent mutations in KRas in various tumor types made KRas a highly attractable target of the
pharmaceutical industry for cancer therapy. Notwithstanding thirty years of large scale discovery efforts to develop inhibitors of KRas for treating cancer, no KRas inhibitor has demonstrated sufficient safety and/or efficacy to obtain regulatory approval (e.g., see McCormick (2015) Clin Cancer Res. 21 (8): 1797-1801).
[005] Compounds that inhibit KRas activity are still highly desirable and under investigation, including those that disrupt effectors such as guanine nucleotide exchange factors (e.g., see Sun et al., (2012) Agnew Chem lnt Ed Engl. 51(25):6140-6143 doi: 10.1002/anie201201358) as well as those that target KRas G12C (e.g., see Ostrem et al., (2013) Nature 503:548-551). Clearly there remains a continued interest and effort to develop inhibitors of KRas, particularly inhibitors of activating KRas mutants, including KRas G12C.
[006] While the KRas G12C inhibitors disclosed herein are potent inhibitors of KRas G12C enzymatic activity and exhibit single agent activity inhibiting the in vitro proliferation of cell lines harboring a KRas G12C mutation, the relative potency and/or observed maximal effect of any given KRas G12C inhibitor can vary between KRas mutant cell lines. The reason or reasons for the range of potencies and observed maximal effect is not fully understood but certain cell lines appear to possess differing intrinsic resistance. Thus, there is a need to develop alternative approaches to maximize the potency, efficacy, therapeutic index and/or clinical benefit of KRas G12C inhibitors in vitro and in vivo.
SOS1 Inhibitors
[007] The Ras family comprises v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRas), neuroblastoma RAS viral oncogene homolog (NRAS), and Harvey murine sarcoma virus oncogene (HRas) and critically regulates cellular division, growth and function in normal and altered states including cancer (see e.g., Simanshu et al. Cell, 2017. 170(1): p. 17-33; Matikas et al., Crit Rev Oncol Hematol, 2017. 110: p. 1-12). RAS proteins are activated by upstream signals, including receptor tyrosine kinases (RTKs), and transduce signals to several downstream signaling pathways such as the mitogen-activated protein kinase (MAPK)/extracellular signal- regulated kinases (ERK) pathway. Hyperactivation of RAS signaling is frequently observed in cancer as a result of mutations or alterations in RAS genes or other genes in the RAS pathway.
The identification of strategies to inhibit RAS and RAS signaling are predicted to be useful for the treatment of cancer and RAS-regulated disease states.
[008] RAS proteins are guanosine triphosphatases (GTPases) that cycle between an inactive, guanosine diphosphate (GDP)-bound state and an active guanosine triphosphate (GTP)-bound state. RAS proteins exhibit both intrinsic GTP hydrolysis and nucleotide exchange, which is further enhanced by extrinsic GTPase activating proteins (GAPs) and guanine echange factors (GEFs). Son of sevenless homolog 1 (SOS1) is a GEF that mediates the exchange of GDP for GTP, thereby activating RAS proteins. This regulation through GAPs and GEFs is the mechanism whereby activation and deactivation are tightly regulated under normal conditions. Mutations at several residues in all three RAS proteins are frequently observed in cancer and result in RAS remaining predominantly in the activated state (Sanchez-Vega et al., Cell, 2018. 173: p. 321-337 Li et al., Nature Reviews Cancer, 2018. 18: p. 767-777). Mutations at codon 12 and 13 disrupt the GTP hydrolysis and exchange rate of RAS proteins. Recent biochemical analyses demonstrated these mutated proteins still require nucleotide cycling for activation based on their intrinsic GTPase activity and may exhibit partial sensitivity to extrinsic GAPs and GEFs. As such, mutant RAS proteins are sensitive to inhibition of upstream factors such as the SOS1 GEF (Hillig, 2019; Patricelli, 2016; Lito, 2016; Nichols, 2018)
[009] The three main RAS-GEF families that have been identified in mammalian cells are SOS, RAS-GRF and RAS-GRP (Rojas, 2011). RAS-GRF and RAS-GRP are expressed in the cells of the central nervous system and hematopoietic cells, respectively, while the SOS family is ubiquitously expressed and is responsible for transducing RTK signaling. The SOS family comprises SOS1 and SOS2 and these proteins share approximately 70% sequence identity. SOS1 appears to be much more active than SOS2 due to the rapid degradation of SOS2. The mouse SOS2 knockout is viable whereas the SOS1 knockout is embryonic lethal. A tamoxifen-inducible SOS1 knockout mouse model was used to interrogate the role of SOS1 and SOS2 in adult mice and demonstrated the SOS1 knockout was viable but the SOS 1/2 double knockout was not viable (Baltanas, 2013) suggesting functional redundancy and that selective inhibition of SOS1 may have a sufficient therapeutic index for the treatment of SOS1 - RAS activated diseases.
[0010] SOS proteins are recruited to phosphorylated RTKs through an interaction with growth factor receptor bound protein 2 (GRB2). Recruitment to the plasma membrane places SOS in
close proximity to RAS and enables SOS-mediated RAS activation. SOS proteins bind to RAS through a catalytic binding site that promotes nucleotide exchange as well as through an allosteric site that binds GTP -bound RAS-family proteins which increases the catalytic function of SOS (Freedman et al., Proc. Natl. Acad. Sci, USA 2006. 103(45): p. 16692-97). Binding to the allosteric site relieves steric occlusion of the catalytic site and is therefore required for full activation of the catalytic site. Retention of the active conformation at the catalytic site following interaction with the allosteric site is maintained in isolation due to strengthened interactions of key domains in the activated state. SOS1 mutations are found in Noonan syndrome and several cancers including lung adenocarcinoma, embryonal rhabdomyosarcoma, Sertoli cell testis tumor and granular cell tumors of the skin (see e.g., Denayer, E., et al, Genes Chromosomes Cancer, 2010. 49(3): p. 242-52).
[0011] GTPase-activating proteins (GAPs) are proteins that stimulate the low intrinsic GTPase activity of RAS family members and therefore converts active GTP -bound RAS proteins into inactive, GDP-bound RAS proteins (e.g., see Simanshu, D.K., Cell, 2017, Ras Proteins and their Regulators in Human Disease). While activating alterations in the phosphatase PTPN11(SHP2) and the GEF SOS1 occur in cancers, inactivating mutations and loss-of-function alterations in the GAP neurofibromin 1 (NF-1) also occur creating a state where SO SI activity is unopposed and activity downstream of the pathway through RAS proteins is elevated.
MEK Inhibitors
[0012] The mitogen-activated protein kinase (MAPK) signaling pathway is involved in the regulation of various cellular activities, including , but not limited to cell proliferation, survival, differentiation, and motility. The classical MAPK pathway consists of Ras (a family of related proteins which is expressed in all animal cell lineages and organs), Raf (a family of three serine/threonine-specific protein kinases that are related to retroviral oncogenes), MEK (mitogen-activated protein kinase kinase), and ERK (extracellular signal-regulated kinases), sequentially relaying proliferative signals generated at the cell surface receptors into the nucleus through cytoplasmic signaling.
[0013] MEK inhibitors target the Ras/Raf/MEK/ERK signaling pathway, thereby inhibiting cell proliferation and inducing apoptosis.
[0014] The MAPK pathway is one of the most commonly mutated oncogenic pathways in cancer, Deregulation of this pathway is frequently observed and plays a central role in the carcinogenesis and maintenance of several cancers, including melanoma, pancreatic, lung, colorectal, and breast cancers, (e.g., Neuzillet et al., (2014) Pharmacology & Therapeutics 141:160-171).
[0015] Several inhibitors exhibiting activity against MEK have been developed, and a number of these inhibitors are or have been inventigated in human clinical trials. Examples of MEK inhibitors suitable for the provided compositions and methods include, but are not limited to selumetinib, 6-(4-bromo-2-chl oroanilino)-7-fluoro-N-(2 -hydroxy ethoxy)-3- methylbenzimidazole-5-carboxamide; AZD8330, 2-(2-fluoro-4-iodoanilino)-N-(2- hydroxyethoxy)-l,5-dimethyl-6-oxopyridine-3-carboxamide; PD0325901, N-[(2R)-2,3- dihydroxypropoxy]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide; PD318088, 5-bromo-N- (2,3-dihydroxypropoxy)-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide; refametinib, N-[3,4- difluoro-2-(2-fluoro-4-iodoanilino)-6-methoxyphenyl] - 1 - [(2 S)-2, 3 - dihydroxypropyl]cyclopropane-l -sulfonamide; binimetinib, 6-(4-bromo-2-fluoroanilino)-7- fluoro-N-(2-hydroxyethoxy)-3-methylbenzimidazole-5-carboxamide; R04987655, 3,4-difluoro- 2-(2-fluoro-4-iodoanilino)-N-(2-hydroxyethoxy)-5-[(3-oxooxazinan-2-yl)methyl]benzamide,
R05126766 (VS-6766), 3-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-4-methyl- 7-pyrimidin-2-yloxychromen-2-one; WX-554, HL-085; ClnQ-03; G-573, 7-fluoro-3-(2-fluoro-4- iodoanilino)-N-[(2S)-2-hydroxypropoxy]furo[3 ,2-c]pyridine-2-carboxamide; PD 184161, 5- bromo-2-(2-chloro-4-iodoanilino)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide;
R05068760, (2S,3S)-2-[(4R)-4-[4-[(2R)-2,3-dihydroxypropoxy]phenyl]-2,5-dioxoimidazolidin- l-yl]-N-(2-fluoro-4-iodophenyl)-3-phenylbutanamide; SL327, (Z)-3 -amino-3 -(4- aminophenyl)sulfanyl-2-[2-(trifluoromethyl)phenyl]prop-2-enenitrile; MEK162 (Arry-162), 5- ((4-bromo-2-fluorophenyl)amino)-4-fluoro-N-(2-hydroxy ethoxy)- 1 -methyl- 1H- benzo[d]imidazole-6-carboxamide; Tak-733, (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-((2-fluoro- 4-iodophenyl)amino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione; GDC-0623, 5-((2- fluoro-4-iodophenyl)amino)-N-(2-hydroxyethoxy)imidazo[l,5-a]pyridine-6-carboxamide;
U0126, (2E,3E)-2-(amino((2-aminophenyl)thio)methylene)-3-(amino((3- aminophenyl)thio)methylene)succinonitrile; trametinib, N-(3-(3-cyclopropyl-5-((2-fluoro-4- iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-l(2H)-
yl)phenyl)acetamide; BI-847325, (E)-3-(3-(((4-
((dimethylamino)methyl)phenyl)amino)(phenyl)methylene)-2-oxoindolin-6-yl)-N- ethylpropiolamide; pimasertib, (S)-N-(2,3-dihydroxypropyl)-3-((2-fluoro-4- iodophenyl)amino)isonicotinamide; BIX02189, (Z)-3-(((3-
((dimethylamino)methyl)phenyl)amino)(phenyl)methylene)-N,N-dimethyl-2-oxoindoline-6- carboxamide; cobimetinib, (3, 4-difluoro-2-((2-fluoro-4-iodophenyl)amino)phenyl)(3 -hydroxy-3- (piperidin-2-yl)azetidin-l-yl)methanone; PD-98059, 2-(2-amino-3-methoxyphenyl)-4H- chromen-4-one; APS-2-79, 6,7-dimethoxy-N-(2-methyl-4-phenoxyphenyl)quinazolin-4-amine; PD 198306, N-(cyclopropylmethoxy)-3,4,5-trifluoro-2-(4-iodo-2-methylbenzyl)benzamide; CI- 1040, 2-(2-chloro-4-iodobenzyl)-N-(cyclopropylmethoxy)-3,4-difluorobenzamide; SL327, (Z)-3- amino-3-((4-aminophenyl)thio)-2-(2-(trifluorc>rnethyl)phenyl)acrylonitrile; and BIX02188, (Z)- 3-(((3-((dimethylamino)methyl)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6- carboxamide.
[0016] Structures of these MEK inhibitors can be found, for example, in Cheng et al, Current Development Status of MEK Inhibitors, Molecules 2017, 22, 1551, as well as in U.S. Patents 10,370, 374 and 10,323,035, as well as in US Patent Application Publication Nos:
20190144382; 20180370948; 20180296533; 20180147192; 20180118715; 20170231963; 20170183348; 20170183333; 20170166523; 20170101408; 20170096388; 20160331753; 20160168103; 20160168102; 20160136150; 20160108041; 20150141399; 20150133424; 20150051209; 20140378466; 20140275527; 20140135519; 20140128442; 20140080804; 20130150573; 20130018075; 20120238599; 20120208859; 20120107307; 20120022076; 20110288092; 20110263558; 20110190257; 20110183981; 20110172191; 20110158971; 20110124622; 20110112152; 20110060049; 20110021558; 20100331334; 20100267710; 20100261718; 20100261717; 20100260714; 20100256149; 20100249096; 20100197676; 20100179124; 20100063053; 20090291961; 20090264411; 20090233915; 20090215834; 20090209542; 20090156576; 20090149437; 20090143579; 20090143389; 20090131435; 20090082457; 20090030058; 20080306063; 20080280957; 20080255133; 20080177082; 20080171778; 20080166359; 20080058340; 20070299063; 20070293544; 20070287737; 20070287709; 20070244164; 20070238710; 20070213367; 20070172843; 20070112038; 20070105859; 20060211073; 20060194802; 20060189808; 20060189668; 20060189649;
20060154990; 20060106225; 20060089382; 20060052608; 20050256123; 20050250782 and 20050153942, the contents of which are hereby incorporated by reference in their entirety.
[0017] One of the MEK inhibitors suitable for the provided compositions and methods is VS- 6766 which has the following structure:
3-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-4-methyl-7-pyrimidin-2- yloxychromen-2-one
[0018] Methods for manufacturing MEK inhibitors, or pharmaceutically acceptable salts or pharmaceutical compositions thereof are well known to those skilled in the art and MEK inhibitors may be obtained from a wide-variety of commercial suppliers, in forms suitable for both research or human use. In addition, suitable MEK inhibitors for use in the compositions and methods disclosed herein and methods for preparing such inhibitors are disclosed in US Patent Application Publication Nos: 20190144382; 20180370948; 20180296533; 20180147192; 20180118715; 20170231963; 20170183348; 20170183333; 20170166523; 20170101408; 20170096388; 20160331753; 20160168103; 20160168102; 20160136150; 20160108041; 20150141399; 20150133424; 20150051209; 20140378466; 20140275527; 20140135519; 20140128442; 20140080804; 20130150573; 20130018075; 20120238599; 20120208859; 20120107307; 20120022076; 20110288092; 20110263558; 20110190257; 20110183981; 20110172191; 20110158971; 20110124622; 20110112152; 20110060049; 20110021558; 20100331334; 20100267710; 20100261718; 20100261717; 20100260714; 20100256149; 20100249096; 20100197676; 20100179124; 20100063053; 20090291961; 20090264411; 20090233915; 20090215834; 20090209542; 20090156576; 20090149437; 20090143579; 20090143389; 20090131435; 20090082457; 20090030058; 20080306063; 20080280957; 20080255133; 20080177082; 20080171778; 20080166359; 20080058340; 20070299063; 20070293544; 20070287737; 20070287709; 20070244164; 20070238710; 20070213367; 20070172843; 20070112038; 20070105859; 20060211073; 20060194802; 20060189808;
20060189668; 20060189649; 20060154990; 20060106225; 20060089382; 20060052608; 20050256123; 20050250782 and 20050153942.
SUMMARY OF THE INVENTION
[0019] The combination therapy of the present invention, in one aspect, synergistically increases the potency of KRas G12C inhibitors resulting in improved efficacy of KRas G12C inhibitors disclosed herein. The combination therapy of the present invention, in another aspect, provides improved clinical benefit to patients compared to treatment with KRas G12C inhibitors disclosed herein as a single agent.
[0020] Thus in one aspect of the invention there are provided therapeutically effective combinations of a SOS1 inhibitor such as those described in US provisional patent applications 62/951,812, 62/975,645, 63/044,802, 62/980,790 and 63/057,563 (and corresponding U.S. and international applications and publications including PCT/US20/66003, PCT/US21/19184, PCT/US21/43309 and US 17/127,582) as described in greated detail herein, for instance:
Me Me
V"sA i
(7Z)-2-mcthyl-3-( 1 -((4-mcthyl-7-morpholinopyrido|3.4-£/|pyridazin- 1 -yl)amino)cthyl)bcnzonitrilc.
3 -((//)- 1 -((7 -((.V)-hcxahydropyrazino [2, 1 -c] [ 1 ,4]oxazin-8( l//)-yl)-4-mcthylpyrido [3 ,4-t/Jpyridazin- 1 - yl)amino)ethyl)-2-methylbenzonitrile,
Me"
(i?)-3 -( 1 -((7 -(3 -(dimethylamino)-3 -methylazetidin- 1 -yl)-4-methylpyrido [3 ,4-<2]pyridazin- 1 - yl)amino)ethyl)-2-methylbenzonitrile,
Me Me
(i?)-2 -methyl-3 -( 1 -((4-methyl-7 -(4-methylpiperazin- 1 -yl)pyrido [3 ,4-<2]pyridazin- 1 - yl)amino)ethyl)benzonitrile,
_e
Et. CM e
(R)- 3-( 1 -((7-(4-ethylpiperazin- 1 -yl)-4-mcthylpyrido| 3.4-£/|pyridazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile,
!V!e Me
(//)-2-mcthyl-3-( 1 -((4-methyl-7-(piperazin- 1 -yl)pyrido|3.4-£/|pyridazin- 1 -yl)amino)ethyl)benzonitrile,
Me Me
CM
Mex
Me
3 -((//)- 1 -((7 -((.V)-3 -(dimethylamino)pyrrolidin- 1 -yl)-4-methylpyrido [3 ,4-t/Jpyridazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile,
Me Me
(R)- 3 -( 1 -((6-fluoro-4-methyl-7-(4-methylpiperazin- 1 -yl)phthalazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile, or a pharmaceutically acceptable salt thereof, and the KRas G12C inhibitor compound 2-[(2iS)-4-[7-(8-chloro-l-naphthyl)-2-[[(2,S)-l- methyl pyrrol idin-2-yl]methoxy]-6,8-dihydro-5//-pyrido[3,4-6/]pyri mi din-4-yl]- l -(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849, and also known as adagrasib): or a pharmaceutically acceptable salt thereof.
[0021] In another aspect of the invention there are provided therapeutically effective combinations of a SOS1 inhibitor such as BI1701963 or a pharmaceutically acceptable salt
thereof, and the KRas G12C inhibitor compound 2-[(25)-4-[7-(8-chloro-l-naphthyl)-2-[[(25)-l- methyl pyrrol idin-2-yl]methoxy]-6,8-dihydro-5//-pyrido[3,4-6/]pyri mi din-4-yl]- l -(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849, and also known as adagrasib): or a pharmaceutically acceptable salt thereof.
[0022] In one aspect, the invention provides a therapeutically effective combination of: the SOS1 inhibitor (f?)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4-<i]pyridazin-l- yl)amino)ethyl)benzonitrile (also known as MRTX0902), having the formula:
Me IVSe
, or a pharmaceutically acceptable salt thereof; and a KRas G12C inhibitor compound 2-[(25)-4-[7-(8-chloro-l-naphthyl)-2-[[(25)-l- methyl pyrrol idin-2-yl]methoxy]-6,8-dihydro-5//-pyrido[3,4-6/]pyri mi din-4-yl]- l -(2-fluoroprop-
2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849, and also known as adagrasib).
[0023] In another aspect, the invention provides a therapeutically effective combination of:
the SOS1 inhibitor (f?)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4-<i]pyridazin-l- yl)amino)ethyl)benzonitrile (also known as MRTX0902), having the formula:
!$e l¥!e
, or a pharmaceutically acceptable salt thereof; a KRas G12C inhibitor compound 2-[(25)-4-[7-(8-chloro-l-naphthyl)-2-[[(25)-l- methyl pyrrol idin-2-yl]methoxy]-6,8-dihydro-5//-pyrido[3,4-6/]pyri mi din-4-yl]- l -(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849, and also known as adagrasib); and the MEK inhibitor [[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-4-methyl-7- pyrimidin-2-yloxychromen-2-one (also known as VS-6766) which has the following structure:
, or a pharmaceutically acceptable
[0024] In another aspect of the invention, pharmaceutical compositions are provided for use in the methods comprising a therapeutically effective amount of a combination of a SOS1 inhibitor such as (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-l- yl)amino)ethyl)benzonitrile, 3-((R)-l-((7-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(l-((7-(3- (dimethylamino)-3-methylazetidin-l-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2- methylbenzonitrile, (R)-2-methyl-3-(l-((4-methyl-7-(4-methylpiperazin-l-yl)pyrido[3,4- d]pyridazin-l-yl)amino)ethyl)benzonitrile, (R)-3-(l-((7-(4-ethylpiperazin-l-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(l-((4- methyl-7-(piperazin-l-yl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile, 3-((R)-l-((7- ((S)-3-(dimethylamino)pyrrolidin-l-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-
methylbenzonitrile or (f?)-3-(l-((6-fluoro-4-methyl-7-(4-methylpiperazin-l-yl)phthalazin-l- yl)amino)ethyl)-2-methylbenzonitrile, or a SOS1 inhibitor such as BI1701963, and the KRas G12C inhibitor compound adagrasib, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.
[0025] In some embodiments, the methods may further comprise administering MEK inhibitors to the subject in need thereof, so that the subject is being administered adagrasib, a SOS1 inhibitor, and a MEK inhibitor, for example VS-6766.
[0026] In one aspect of the invention, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a SOS1 inhibitor such as (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4- djpyridazin- 1 -yl)amino)ethyl)benzonitrile, 3 -((R)- 1 -((7-((S)-hexahydropyrazino[2, 1 - c][l,4]oxazin-8(lH)-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2- methylbenzonitrile, (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)-4-methylpyrido[3,4- d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(l-((4-methyl-7-(4- methylpiperazin-l-yl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile, (R)-3-(l-((7-(4- ethylpiperazin- 1 -yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 -yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(l-((4-methyl-7-(piperazin-l-yl)pyrido[3,4-d]pyridazin-l- yl)amino)ethyl)benzonitrile, 3-((R)-l-((7-((S)-3-(dimethylamino)pyrrolidin-l-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile or (i?)-3-(l-((6-fluoro-4- methyl-7-(4-methylpiperazin-l-yl)phthalazin-l-yl)amino)ethyl)-2-methylbenzonitrile,
[0027] or a SOS1 inhibitor such as BI1701963, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the KRas G12C inhibitor adagrasib, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
[0028] In one embodiment, the cancer is a KRas G12C-associated cancer. In one embodiment, the KRas G12C-associated cancer is lung cancer.
[0029] In some aspects of the invention, KRas G12C inhibitor compounds and SOS1 inhibitors are the only active agents in the provided compositions and methods.
[0030] Examples of SOS1 inhibitors suitable for the provided compositions and methods include, but are not limited to (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4- djpyridazin- 1 -yl)amino)ethyl)benzonitrile, 3 -((R)- 1 -((7-((S)-hexahydropyrazino[2, 1 - c][l,4]oxazin-8(lH)-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2- methylbenzonitrile, (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)-4-methylpyrido[3,4- d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(l-((4-methyl-7-(4- methylpiperazin-l-yl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile, (R)-3-(l-((7-(4- ethylpiperazin- 1 -yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 -yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(l-((4-methyl-7-(piperazin-l-yl)pyrido[3,4-d]pyridazin-l- yl)amino)ethyl)benzonitrile, 3-((R)-l-((7-((S)-3-(dimethylamino)pyrrolidin-l-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile and (R)-3-(l-((6-fluoro-4- methyl-7-(4-methylpiperazin-l-yl)phthalazin-l-yl)amino)ethyl)-2-methylbenzonitrile, and pharmaceutically acceptable salts thereof.
[0031] . Other examples of SOS1 inhibitors suitable for the provided compositions and methods include BI 1701963.
[0032] In yet another aspect, the invention provides a method for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a combination of the KRas G12C inhibitor adagrasib:
or a pharmaceutically acceptable salt thereof, and a SOS1 inhibitor.
[0033] In one embodiment, the SOS1 inhibitor has the following structure:
pharmaceutically acceptable salt thereof.
[0034] In yet another aspect, the method also comprises contacting the cell with a compound having the following structure:
pharmaceutically acceptable salt thereof.
[0035] In yet another aspect, the invention provides for methods for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor, comprising contacting the cancer cell with a therapeutically effective amount of a combination of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a SOS1 inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo. In one embodiment, the method comprises administering to a subject undergoing KRas G12C treatment with an effective amount of a combination the KRas G12C inhibitor adagrasib or a pharmaceutically acceptable salt thereof, and a SOS1 inhibitor, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor.
[0036] In one embodiment, the method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor, comprises contacting the cancer cell with a therapeutically effective amount of a combination of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a SOS1 inhibitor having the following structure:
pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
[0037] In yet another embodiment, the method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor also comprises contacting the cancer cell with a compound having the following structure:
[0038] Also provided herein are methods for treating cancer in a subject in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the SO SI inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to adagrasib.
[0039] Also provided herein are kits comprising a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. Also provided is a kit comprising a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, for use in treating a KRas G12C cancer.
[0040] In a related aspect, the invention provides a kit containing a dose of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof in an amount effective to inhibit proliferation of cancer cells in a subject. The kit in some cases includes an insert with instructions for administration of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. The insert may provide a user with one set of instructions for using the a SOS1 inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof in combination with the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
[0041] In some aspects of any of the methods described herein, before treatment with the compositions or methods of the invention, the patient was treated with one or more of a chemotherapy, a targeted anticancer agent, radiation therapy, and surgery, and optionally, the prior treatment was unsuccessful; and/or the patient has been administered surgery and optionally, the surgery was unsuccessful; and/or the patient has been treated with a platinum- based chemotherapeutic agent, and optionally, the patient has been previously determined to be non-responsive to treatment with the platinum-based chemotherapeutic agent; and/or the patient has been treated with a kinase inhibitor, and optionally, the prior treatment with the kinase inhibitor was unsuccessful; and/or the patient was treated with one or more other therapeutic agent(s).
BRIEF DESCRIPTION OF THE DRAWINGS
[0042] Fig. 1 is a chart of tumor growth inhibition of MIA PaCA-2 tumor bearing mice by MRTX0902, adagrasib, and a combination of MRTX0902 and adagrasib.
[0043] Fig. 2 is a chart of tumor growth inhibition of MIA PaCA-2 tumor bearing mice by MRTX0902, adagrasib, and a combination of MRTX0902 and adagrasib.
[0044] Fig. 3 is a chart of tumor growth inhibition of MIA PaCA-2 tumor bearing mice by MRTX2006, adagrasib, and a combination of MRTX0902 and adagrasib.
[0045] Fig. 4 is a chart of tumor growth inhibition of MIA PaCA-2 tumor bearing mice by MRTX4197, adagrasib, and a combination of MRTX0902 and adagrasib.
[0046] Fig. 5 is a chart of tumor growth inhibition of LU99 tumor bearing mice by MRTX0902, adagrasib, and a combination of MRTX0902 and adagrasib.
[0047] Fig. 6 is a chart of tumor growth inhibition of NC1-H2122 tumor bearing mice by MRTX0902; adagrasib; and a combination of MRTX0902 and adagrasib.
[0048] Fig. 7 is a chart of tumor growth inhibition of NC1-H2122 tumor bearing mice by MRTX0902, adagrasib, a combination of MRTX0902 and VS-6766; and a combination of VS- 6766 and adagrasib.
[0049] Fig. 8 is a chart of tumor growth inhibition of CR6256 tumor bearing mice by MRTX0902; adagrasib; and a combination of MRTX0902 and adagrasib.
[0050] Fig. 9 is a bar chart demonstrating efficacy of a combination of MRTX849 and MRTX0902 in a variety of human tumor xenograft KRas G12C models.
DETAILED DESCRIPTION OF THE INVENTION
[0051] The present invention relates to combination therapies for treating KRas G12C cancers. In particular, the present invention relates to methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a SOS1 inhibitor or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, pharmaceutical compositions comprising therapeutically effective amounts of the inhibitors, kits comprising the compositions and methods of use therefor.
[0052] Combinations of the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, with a KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, synergistically increase the potency of the KRas G12C inhibitor compound adagrasib against cancer cells that express KRas G12C
thereby increasing the efficacy and therapeutic index of the KRas G12C inhibitor compound adagrasib or pharmaceutically acceptable salts thereof.
DEFINITIONS
[0053] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated by reference.
[0054] As used herein, “KRas G12C” refers to a mutant form of a mammalian KRas protein that contains an amino acid substitution of a cysteine for a glycine at amino acid position 12. The assignment of amino acid codon and residue positions for human KRas is based on the amino acid sequence identified by UniProtKB/Swiss-Prot P01116: Variant p.Glyl2Cys.
[0055] As used herein, a “KRas G12C inhibitor” refers to compounds of the present invention that are represented by Formula (I), Formula I-A and Formula I-B as described in WO2019099524), or pharmaceutically acceptable salts thereof (e.g., Example Nos 234, 359, 478 or 507, or a pharmaceutically acceptable salt thereof).. These compounds are capable of negatively modulating or inhibiting all or a portion of the enzymatic activity of KRas G12C. The KRas G12C inhibitors of the present invention interact with and irreversibly bind to KRas G12C by forming a covalent adduct with the sulfhydryl side chain of the cysteine residue at position 12 resulting in the inhibition of the enzymatic activity of KRas G12C. Adagrasib is an example of a KRas G12C inhibitor,
[0056] A "KRas G12C-associated disease or disorder" as used herein refers to diseases or disorders associated with or mediated by or having a KRas G12C mutation. A non-limiting example of a KRas G12C-associated disease or disorder is a KRas G12C-associated cancer.
[0057] As used herein, “SOS1” refers to the Son of sevenless homolog 1 protein encoded by the SOS1 gene that is involved in signaling through RAS pathways.
[0058] As used herein, a “SOS1 inhibitor” refers to a compound that is capable of negatively modulating or inhibiting all or a portion of the interaction between KRAS and SOS1.
[0059] As used herein, the term “subject,” “individual, ” or “patient, ” used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the patient is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer having a KRas G12C mutation (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a KRas G12C mutation (e.g., as determined using a regulatory agency-approved assay or kit). The subject can be a subject with a tumor(s) that is positive for a KRas G12C mutation (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a KRas G12C mutation (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a KRas G12C gene-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a KRas G12C mutation (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein).
[0060] The term “pediatric patient” as used herein refers to a patient under the age of 16 years at the time of diagnosis or treatment. The term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994.
[0061] In some embodiments of any of the methods or uses described herein, an assay is used to determine whether the patient has KRas G12C mutation using a sample (e.g., a biological sample or a biopsy sample such as a paraffin-embedded biopsy sample) from a patient (e.g., a patient suspected of having a KRas G12C-associated cancer, a patient having one or more
symptoms of a KRas G12C-associated cancer, and/or a patient that has an increased risk of developing a KRas G12C-associated cancer) can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR, quantitative real-time RT-PCR, allele-specific genotyping or ddPCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen-binding fragment thereof.
[0062] The term “regulatory agency” is a country’s agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA).
[0063] As used herein, “an effective amount” of a compound is an amount that is sufficient to negatively modulate or inhibit the activity of the desired target, i.e., SOS1 or KRas G12C.
Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
[0064] As used herein, a "therapeutically effective amount" of a compound is an amount that is sufficient to ameliorate, or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of SOS1 or KRas G12C. Such amount may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
[0065] As used herein, a "therapeutically effective amount of a combination" of two compounds is an amount that together synergistically increases the activity of the combination in comparison to the therapeutically effective amount of each compound in the combination, i.e., more than merely additive. Alternatively, in vivo, the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, results in an increased duration of overall survival (“OS”) in subjects relative to treatment with only the KRas G12C inhibitor. In one embodiment, the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas
G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, results in an increased duration of progression-free survival (“PFS”) in subjects relative to treatment with only the KRas G12C inhibitor. In one embodiment, the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, results in increased tumor regression in subjects relative to treatment with only the KRas G12C inhibitor. In one embodiment, the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, results in increased tumor growth inhibition in subjects relative to treatment with only the KRas G12C inhibitor. In one embodiment, the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, results in an improvement in the duration of stable disease in subjects compared to treatment with only the KRas G12C inhibitor. The amount of each compound in the combination may be the same or different than the therapeutically effective amount of each compound when administered alone as a monotherapy as long as the combination is synergistic. Such amounts may be administered as a single dosage or may be administered according to a regimen, whereby it is effective.
[0066] As used herein, “treatment” means any manner in which the symptoms or pathology of a condition, disorder or disease are ameliorated or otherwise beneficially altered. Treatment also encompasses any pharmaceutical use of the compositions herein.
[0067] As used herein, “amelioration” of the symptoms of a particular disorder by administration of a particular pharmaceutical composition refers to any lessening, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the composition.
[0068] As used herein, the term “about” when used to modify a numerically defined parameter (e.g., the dose of a KRas inhibitor or a SOS1 inhibitor or a pharmaceutically acceptable salt
thereof, or the length of treatment time with a combination therapy described herein) means that the parameter may vary by as much as 10% below or above the stated numerical value for that parameter. For example, a dose of about 5 mg/kg may vary between 4.5 mg/kg and 5.5 mg/kg. “About” when used at the beginning of a listing of parameters is meant to modify each parameter. For example, about 0.5 mg, 0.75 mg or 1.0 mg means about 0.5 mg, about 0.75 mg or about 1.0 mg. Likewise, about 5% or more, 10% or more, 15% or more, 20% or more, and 25% or more means about 5% or more, about 10% or more, about 15% or more, about 20% or more, and about 25% or more.
KRas G12C INHIBITOR COMPOUNDS
[0069] In one aspect of the invention, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
[0070] In one embodiment, the KRas G12C inhibitor is:
(also referred to as adagrasib, MRTX849, and Eaxmple 478 in WO2019099524) or a pharmaceutically acceptable salt thereof.
[0071] The KRas G12C inhibitors used in the methods of the present invention may have one or more chiral center and may be synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures or the individual components/isomers may be separated using commercially
available reagents and conventional methods for isolation of stereoisomers and enantiomers well-known to those skilled in the art, e.g., using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatographic HPLC columns according to the manufacturer’s instructions. Alternatively, compounds of the present invention may be synthesized using optically pure, chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Unless otherwise indicated, whenever the specification, including the claims, refers to compounds of the invention, the term “compound” is to be understood to encompass all chiral (enantiomeric and diastereomeric) and racemic forms.
[0072] In one embodiment, the KRas G12C inhibitor compound adagrasib used in the methods include salts of the above compounds, for instance salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid, and salts formed from quaternary ammoniums of the formula — NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methyl sulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
[0073] Methods for manufacturing the KRas G12C inhibitors disclosed herein are known. For example, commonly owned published international PCT application numbers W02017201161, and WO 2019099524 describe general reaction schemes for preparing compounds including adagrasib and also provide detailed synthetic routes for the preparation of these compounds.
SOS1 INHIBITOR COMPOUNDS
[0074] In one embodiment, the SOS1 inhibitor is a compound selected from (R)-2-methyl-3-(l- ((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile, 3-((R)-l-((7- ((S)-hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(lH)-yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 - yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)-
4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(l-((4- methyl-7-(4-methylpiperazin-l-yl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile, (R)-3- ( 1 -((7-(4-ethylpiperazin- 1 -yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile, (R)-2-methyl-3-(l-((4-methyl-7-(piperazin-l-yl)pyrido[3,4-d]pyridazin-l- yl)amino)ethyl)benzonitrile, 3-((R)-l-((7-((S)-3-(dimethylamino)pyrrolidin-l-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (i?)-3-(l-((6-fluoro-4- methyl-7-(4-methylpiperazin-l-yl)phthalazin-l-yl)amino)ethyl)-2-methylbenzonitrile, or a pharmaceutically acceptable salt thereof; or selected from the compounds described in US provisional patent applications 62/951,812, 62/975,645, 63/044,802, 62/980,790 and 63/057,563 (and corresponding international applications and publications including PCT/US20/06603 and US 17/127,582 ) as described in greater detail herein.
[0075] In another embodiment, the SOS1 inhibitor is BI1701963.
[0076] In another embodiment the SOS1 inhibitor is a compound of the formula:
[0077] or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, hydroxyl, Cl - C6 alkyl, alkoxy, -N(R6)2, -NR6C(0)R6, -C(0)N(R6)2, -SChalkyl, -S02NR6alkyl, cycloalkyl, -Q- heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are each optionally substituted with one or more R2; each Q is independently a bond, O, or NR6; X is N or CR7; each R2 is independently hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, -N(R6)2, -SCtealkyl, -NR6C(0)C1 - C3 alkyl, -C(0)cycloalkyl, - C(0)heretocyclyl or aryl, wherein the cycloalkyl, the heterocyclyl or the aryl are each optionally substituted with one or more R11; R3 is hydrogen, Cl - C6 alkyl, alkoxy, -N(R10)2, cycloalkyl, haloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the Cl - C6 alkyl, the cycloalkyl, the
heterocyclyl, the aryl, and the heteroaryl are each optionally substituted with one or more R9; Y is a bond or heteroarylene; R4 is aryl or heteroaryl, each optionally substituted with one or more R5; each R5 is independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, Cl - C3 alkyl, haloalkyl, -N(R6)2, -L-N(R6)2 or -SCtealkyl; L is Cl - C3 alkylene; each R6 is independently hydrogen, Cl - C3 alkyl, haloalkyl, or cycloalkyl; R7 is hydrogen, cyano, or alkoxy; R8 is Cl - C2 alkyl or halo-Cl - C2 alkyl; each R9 is independently hydroxy, halogen, amino, cyano, alkoxy, or Cl - C3 alkyl; each R10 is independently hydrogen, Cl - C3 alkyl or cycloalkyl; and each R11 is independently Cl - C3 alkyl or haloalkyl. These compounds include, but are not limited to, compounds such as:
Me
Me
Me
Me
HN
NVV^N 1 N
Me
and pharmaceutically acceptable salts thereof.
[0078] In another embodiment the SOS1 inhibitor is a compound of the formula:
R
R
Y
R
[0079] or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, hydroxy, Cl - C6 alkyl, alkoxy, -N(R6)2, -NR6C(0)R6, -C(0)N(R6)2, -SChalkyl, -S02NR6alkyl, cycloalkyl, -Q-
heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are each optionally substituted with one or more R2; each Q is independently a bond or O; X is N or CR7; each R2 is independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, - N(R6)2, -SCtealkyl, -NR6C(0)R6 Cl - C3 alkyl, haloalkyl, cycloalkyl or aryl; R3 is hydrogen, halogen, cyano, Cl - C6 alkyl, alkoxy, -N(R10)2, -NR10C(O)NR10, -C(O)N(R10)2, -SCkalkyl, - SO2NR10alkyl, -SO2N(R10)2, cycloalkyl, haloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the Cl - C6 alkyl, cycloalkyl, the heterocyclyl, the aryl, and the heteroaryl are each optionally substituted with one or more R9; Y is a bond or heteroarylene; R4 is aryl or heteroaryl, each optionally substituted with one or more R5; each R5 is independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, Cl - C3 alkyl, haloalkyl or -L-N(R6)2; L is Cl - C3 alkylene; each R6 is independently hydrogen, Cl - C3 alkyl or cycloalkyl; R7 is hydrogen or alkoxy; R8 is Cl -C2 alkyl or halo-Cl - C2 alkyl; each R9 is independently hydroxy, halogen, amino, cyano, alkoxy, or Cl - C6 alkyl; each R10 is independently hydrogen, Cl - C3 alkyl or cycloalkyl; and R11 is hydrogen, Cl - C3 alkyl, cycloalkyl, or haloalkyl. These compounds include, but are not limited to, compounds such as:
Me Me Me Me Me
F F F
CFs
Me Me and pharmaceutically acceptable salts thereof.
[0080] In another embodiment the SOS1 inhibitor is a compound of the formula: or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrogen, hydroxyl, Cl - C6 alkyl, alkoxy, -N(R6)2, -NR6C(0)R6, -C(0)N(R6)2, -SChalkyl, -S02NR6alkyl, cycloalkyl, -Q- heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, the heterocyclyl, the aryl, or the heteroaryl are each optionally substituted with one or more R2; each Q is independently a bond,
O or NR6; X is N or CR7; with the proviso that when X is N, R1 is not hydroxyl; each R2 is independently hydroxy, halogen, cyano, hydroxyalkyl, haloalkyl, alkoxy, -N(R6)2, -SCtealkyl, - NR6C(0)C1 - C3 alkyl, -C(0)cycloalkyl, -C(0)heretocyclyl or aryl, wherein the cycloalkyl, the heterocyclyl or the aryl are each optionally substituted with one or more R9; R3 is hydrogen, Cl - C3 alkyl, Cl - C3 haloalkyl, or cycloalkyl; Y is a bond or heteroarylene; R4 is aryl or heteroaryl, each optionally substituted with one or more R5; each R5 is independently hydroxy, halogen, cyano, hydroxyalkyl, alkoxy, Cl - C4 alkyl, haloalkyl, -N(R6)2, -L-N(R6)2 or -SCkalkyl; L is Cl - C3 alkylene; each R6 is independently hydrogen, Cl - C3 alkyl, haloalkyl or cycloalkyl; R7 is hydrogen, cyano or alkoxy; R8 is Cl -C2 alkyl or halo-Cl - C2 alkyl; and each R9 is independently Cl - C3 alkyl or haloalkyl. These compounds include, but are not limited to, compounds such as:
and pharmaceutically acceptable salts thereof.
[0081] In another embodiment, the SOS1 inhibitor is a compound selected from:
IVIe Me i jwS
Me
(f?)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4-<i]pyridazin-l- yl)amino)ethyl)benzonitrile,
Me IVIe
3-((f?)-l-((7-((,S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(l//)-yl)-4-methylpyrido[3,4- d]pyridazin- 1 -yl)amino)ethyl)-2-methylbenzonitrile,
CM
(7?)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)-4-methylpyrido[3,4-<i]pyridazin-l- yl)amino)ethyl)-2-methylbenzonitrile, and
_e svie e
(7?)-2-methyl-3-(l-((4-methyl-7-(4-methylpiperazin-l-yl)pyrido[3,4-<i]pyridazin-l- yl)amino)ethyl)benzonitrile, e svie
(i?)-3-( 1 -((7-(4-ethylpiperazin- 1 -yl)-4-mcthylpyrido| 3.4-£/|pyridazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile,
Me Me
(//)-2-mcthyl-3-( 1 -((4-methyl-7-(piperazin- 1 -yl)pyrido|3.4-£/|pyridazin- 1 -yl)amino)ethyl)benzonitrile, and
Me Me
C n
3 -((//)- 1 -((7 -((.Y)-3 -(dimethylamino)pyrrolidin- 1 -yl)-4-methylpyrido [3 ,4-rijpyridazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile,
Me Me
(R)- 3 -( 1 -((6-fluoro-4-methyl-7-(4-methylpiperazin- 1 -yl)phthalazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile, and pharmaceutically acceptable salts thereof.
[0082] The SOS1 inhibitors used in the methods of the present invention may have one or more chiral center and may be synthesized as stereoisomeric mixtures, isomers of identical constitution that differ in the arrangement of their atoms in space. The compounds may be used as mixtures or the individual components/isomers may be separated using commercially available reagents and conventional methods for isolation of stereoisomers and enantiomers well-known to those skilled in the art, e.g., using CHIRALPAK® (Sigma-Aldrich) or CHIRALCEL® (Diacel Corp) chiral chromatographic HPLC columns according to the manufacturer’s instructions. Alternatively, compounds of the present invention may be synthesized using optically pure, chiral reagents and intermediates to prepare individual isomers or enantiomers. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are within the scope of the invention. Unless otherwise indicated, whenever the specification, including the claims, refers to compounds of the invention, the term “compound” is to be understood to encompass all chiral (enantiomeric and diastereomeric) and racemic forms.
[0083] In one embodiment, the SOS1 inhibitor compound includes its salts, for instance salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid, and salts formed from quaternary ammoniums of the formula — NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
[0084] Methods for manufacturing the SOS1 inhibitors disclosed herein are known. For example, commonly owned application numbers 62/951,812, 62/975,645, 63/044,802, 62/980,790 and 63/057,563, and corresponding international applications and publications PCT/US2020/066003 (W021/127429), PCT/US2021/019184 (WO 2021/173524) and PCT/US2021/043309 (WO 2022/026465), describe general reaction schemes for preparing compounds and also provide detailed synthetic routes for the preparation of these compounds.
PHARMACEUTICAL COMPOSITIONS
[0085] The SOS1 inhibitors and the KRas G12C compound adagrasib or pharmaceutically acceptable salts thereof may be formulated into pharmaceutical compositions.
[0086] In another aspect, the invention provides pharmaceutical compositions comprising a SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, and the KRas G12C inhibitor adagrasib, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient, or diluent that may be used in the methods disclosed herein. The SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, and KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof may be independently formulated by any method well known in the art and may be prepared for administration by any route, including, without limitation, parenteral, oral, sublingual, transdermal, topical, intranasal, intratracheal, or intrarectal. In certain embodiments, SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, and KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, are
administered intravenously in a hospital setting. In one embodiment, administration may be by the oral route.
[0087] The characteristics of the carrier will depend on the route of administration. As used herein, the term "pharmaceutically acceptable" means a non-toxic material that is compatible with a biological system such as a cell, cell culture, tissue, or organism, and that does not interfere with the effectiveness of the biological activity of the active ingredient(s). Thus, compositions may contain, in addition to the inhibitor, diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The preparation of pharmaceutically acceptable formulations is described in, e.g., Remington's Pharmaceutical Sciences, 18th Edition, ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.
[0088] As used herein, the term “pharmaceutically acceptable salt” refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary ammonium salt of the formula — NR+Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, -O-alkyl, toluenesulfonate, methyl sulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).
[0089] The active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. In one embodiment, a dose of the active compound for all of the above-mentioned conditions is in the range from about 0.01 to 300 mg/kg, for example 0.1 to 100 mg/kg per day, and as a further example 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3% wt/wt in
a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.
[0090] The pharmaceutical compositions comprising a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and a KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, may be used in the methods of use described herein.
CO-ADMIN STRATION
[0091] The SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, and the KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, can be formulated into separate or individual dosage forms which can be co-administered one after the other. Another option is that if the route of administration is the same (e.g. oral) two active compounds can be formulated into a single form for co-administration, both methods of co-administration, however, being part of the same therapeutic treatment or regimen.
[0092] The pharmaceutical compositions comprising a SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, and/or a KRas G12C inhibitor, or a pharmaceutically acceptable salt thereof, for use in the methods may be for simultaneous, separate or sequential use. In one embodiment, the SOS1 inhibitor or a pharmaceutically acceptable salt thereof, is administered prior to administration of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt thereof. In another embodiment, the SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, is administered after administration of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt thereof. In another embodiment, the SOS1 inhibitor, or a pharmaceutically acceptable salt thereof, is administered at about the same time as administration of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt thereof.
[0093] Separate administration of each inhibitor, at different times and by different routes, in some cases would be advantageous. Thus, the components in the combination i.e. the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt thereof and the SOS1
inhibitor, or a pharmaceutically acceptable salt thereof, need not be necessarily administered at essentially the same time or in any order.
[0094] Oncology drugs are typically administered at the maximum tolerated dose (“MTD”), which is the highest dose of drug that does not cause unacceptable side effects. In one embodiment, the KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are each dosed at their respective MTDs. In one embodiment, the KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD and the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed in an amount less than its MTD. In one embodiment, the KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at an amount less than its MTD and the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is dosed at its MTD. In one embodiment, the KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof and the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each dosed at less than their respective MTDs. The administration can be so timed that the peak pharmacokinetic effect of one compound coincides with the peak pharmacokinetic effect of the other.
[0095] In one embodiment, a single dose of KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is administered per day (i.e., in about 24 hour intervals) (i.e., QD). In another embodiment, two doses of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered per day (i.e., BID). In another embodiment, three doses of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered per day (i.e., TID).
[0096] In one embodiment, the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is administered QD. In another embodiment the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, are administered BID. In another embodiment, the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, of the invention are administered TID.
[0097] In one embodiment, a single dose of KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof are each administered once daily.
[0098] Examples of SOS1 inhibitors suitable for the provided compositions and methods include those mentioned herein, for example (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4- d]pyridazin- 1 -yl)amino)ethyl)benzonitrile, 3 -((R)- 1 -((7-((S)-hexahydropyrazino[2, 1 - c][l,4]oxazin-8(lH)-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2- methylbenzonitrile, (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)-4-methylpyrido[3,4- d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(l-((4-methyl-7-(4- methylpiperazin-l-yl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile, (R)-3-(l-((7-(4- ethylpiperazin- 1 -yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 -yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(l-((4-methyl-7-(piperazin-l-yl)pyrido[3,4-d]pyridazin-l- yl)amino)ethyl)benzonitrile, 3-((R)-l-((7-((S)-3-(dimethylamino)pyrrolidin-l-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, and (i?)-3-(l-((6-fluoro-4- methyl-7-(4-methylpiperazin-l-yl)phthalazin-l-yl)amino)ethyl)-2-methylbenzonitrile,
[0099] or a pharmaceutically acceptable salt thereof, or a SOS1 inhibitor such as BI1701963.
COMBINATION THERAPIES
[00100] In one aspect of the invention, provided herein are methods of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRasKRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. In one embodiment, the cancer is a KRas G12C-associated cancer. In one embodiment, the KRas G12C-associated cancer is lung cancer.
[00101] In yet another aspect, the invention provides a method for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a combination of the KRas G12C inhibitor adagrasib:
or a pharmaceutically acceptable salt thereof, and a SOS1 inhibitor.
[00102] In one embodiment, the SOS1 inhibitor has the following structure:
pharmaceutically acceptable salt thereof.
[00103] In yet another aspect, the method also comprises contacting the cell with a compound having the following structure:
pharmaceutically acceptable salt thereof.
[00104] In yet another aspect, the invention provides for methods for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor, comprising contacting the cancer cell with an effective amount of a combination of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor.
In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo. In one embodiment, the method comprises administering to a subject undergoing KRas G12C treatment with an effective amount of a combination the KRas G12C inhibitor adagrasib or a
pharmaceutically acceptable salt thereof, and a SOS1 inhibitor, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor.
[00105] In one embodiment, the method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor, comprises contacting the cancer cell with a therapeutically effective amount of a combination of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and a SOS1 inhibitor having the following structure:
pharmaceutically acceptable salt thereof or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
[00106] In yet another embodiment, the method for increasing the sensitivity of a cancer cell to a KRas G12C inhibitor also comprises contacting the cancer cell with a compound having the following structure:
salt thereof.
[00107] In one embodiment, the combination therapy comprises a combination of a compound having the formula:
(adagrasib) or a pharmaceutically acceptable salt thereof, and a SOS1 inhibitor. [00108] In one such embodiment, the SOS1 inhibitor is:
Me Me
(/?)-2-methyl-3-( 1 -((4-methyl -7-morpholinopyrido[3 ,4-i/jpyri dazin-1 - yl)amino)ethyl)benzonitrile.
[00109] In another such embodiment, the SOS1 inhibitor is:
Me Me
3”((i?)-l-((7-(uST)“hexahydropyrazino[2,l-c][l,4]oxazin--8(l/f)--yl)--4-niethylpyrido[3,4” t/jpy ri dazin- 1-yl )ami no)et hy 1 )- 2 -rneth y lb en zon itri 1 e
[00110] In yet another such embodiment, the SOS1 inhibitor is:
(/^)~3-(l-((7~(3-(dimeihylamifio)-3-methylazetidin-l ~yl)~4~methyipyrido[3,4~£:/]pyridazin-l - yi)armno)etbyI)~2~methyibenzoniiriie.
[00111] In still another such embodiment, the SOS1 inhibitor is:
Me Me
(/?)-2~meihy 1 -3 -( 1 -((4-methy i -7~(4~methy ] pi perazin- 1 ~yl)pyrido[3 ,4~<7]py ri dazin- 1 - yl)amino)ethyl)benzonitrile.
[00112] In another embodiment, the SOS1 inhibitor is:
Me Me
(i?)-3-(l-((7-(4-ethylpiperazin-l-yl)-4-methylpyrido[3,4-<i]pyridazin-l-yl)amino)ethyl)-2- methylbenzonitrile.
[00113] In another embodiment, the SOS1 inhibitor is:
Me ¾1e
(7?)-2-methyl-3-(l-((4-methyl-7-(piperazin-l-yl)pyrido[3,4-<i]pyridazin-l- yl)amino)ethyl)benzonitrile.
[00114] In another embodiment, the SOS1 inhibitor is:
Me Me
Me^ f
Me
3 -(( R )- 1 -((7-((5)-3 -(dimethylamino)pyrrolidin- 1 -yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 - yl)amino)ethyl)-2-methylbenzonitrile.
[00115] In another embodiment, the SOS1 inhibitor is:
Me Me
N
(R)- 3 -( 1 -((6-fluoro-4-methyl-7-(4-methylpiperazin- 1 -yl)phthalazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile.
[00116] In still yet another embodiment, the SOS1 inhibitor is BI1701963.
[00117] In yet another embodiment, the invention provides a therapeutically effective combination of: the SOS1 inhibitor (f?)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4-<i]pyridazin-l- yl)amino)ethyl)benzonitrile (also known as MRTX0902), having the formula:
S^e IVSe
, or a pharmaceutically acceptable salt thereof; and a KRas G12C inhibitor compound 2-[(25)-4-[7-(8-chloro-l-naphthyl)-2-[[(25)-l- methyl pyrrol idin-2-yl]methoxy]-6,8-dihydro-5//-pyrido[3,4-6/]pyri mi din-4-yl]- l -(2-fluoroprop-
2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849, and also known as adagrasib).
[00118] In another embodiment, the invention provides a therapeutically effective combination of: the SOS1 inhibitor (f?)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4-<i]pyridazin-l- yl)amino)ethyl)benzonitrile (also known as MRTX0902), having the formula:
Me IVSe
, or a pharmaceutically acceptable salt thereof; a KRas G12C inhibitor compound 2-[(25)-4-[7-(8-chloro-l-naphthyl)-2-[[(25)-l- methyl pyrrol idin-2-yl]methoxy]-6,8-dihydro-5//-pyrido[3,4-6/]pyri mi din-4-yl]- l -(2-fluoroprop- 2-enoyl)piperazin-2-yl]acetonitrile (also known as MRTX849, and also known as adagrasib); and the MEK inhibitor [[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-4-methyl-7- pyrimidin-2-yloxychromen-2-one (also known as VS-6766) which has the following structure:
[00119] As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a cancer cell includes the administration of a combination provided herein to an individual or subject, such as a human, having KRas G12C, as well as, for example, introducing a combination provided herein into a sample containing a cellular or purified preparation containing KRas G12C.
[00120] By negatively modulating the activity of KRas G12C, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12C activity within the cell. The degree of covalent modification of KRas G12C may be monitored in vitro using well known methods, including those described in published international PCT application numbers W02017201161 and WO2019099524. In addition, the inhibitory activity of combination in cells may be monitored, for example, by measuring the inhibition of KRas G12C activity of the amount of phosphorylated ERK to assess the effectiveness of treatment and dosages may be adjusted accordingly by the attending medical practitioner.
[00121] The compositions and methods provided herein may be used for the treatment of a KRas G12C-associated cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the SOS1 inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor. In one embodiment, the KRas G12C-associated cancer is lung cancer.
[00122] In one embodiment, the therapeutically effective amount of the combination of a
SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a
pharmaceutical composition thereof, results in an increased duration of overall survival (“OS”) in subjects relative to treatment with only the KRas G12C inhibitor. In one embodiment, the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, results in an increased duration of progression-free survival (“PFS”) in subjects relative to treatment with only the KRas G12C inhibitor. In one embodiment, the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, results in increased tumor regression in subjects relative to treatment with only the KRas G12C inhibitor. In one embodiment, the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, results in increased tumor growth inhibition in subjects relative to treatment with only the KRas G12C inhibitor. In one embodiment, the therapeutically effective amount of the combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, results in an improvement in the duration of stable disease in subjects compared to treatment with only the KRas G12C inhibitor adagrasib. In one embodiment, the SOS1 inhibitor is selected from (f?)-2-methyl-3-(l-((4-methyl-7- morpholinopyrido[3,4-i/]pyridazin-l-yl)amino)ethyl)benzonitrile, 3-((/s’)- l -((7-((S)- hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(li7)-yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 - yl)amino)ethyl)-2-methylbenzonitrile, (f?)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)- 4-methylpyrido[3,4-i/]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (i?)-2-methyl-3-(l-((4- m ethyl -7-(4-m ethyl pi perazin-1 -yl)pyrido[3,4-i/]pyridazin- l-yl)amino)ethyl)benzonitrile, (R)-3- ( 1 -((7-(4-ethylpiperazin- 1 -yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile, (R)-2-methyl-3-(l-((4-methyl-7-(piperazin-l-yl)pyrido[3,4-d]pyridazin-l- yl)amino)ethyl)benzonitrile, 3-((R)-l-((7-((S)-3-(dimethylamino)pyrrolidin-l-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (i?)-3-(l-((6-fluoro-4- methyl-7-(4-methylpiperazin-l-yl)phthalazin-l-yl)amino)ethyl)-2-methylbenzonitrile, or a
pharmaceutically acceptable salt thereof. In another embodiment, the SOS1 inhibitor is BI1701963.
[00123] In another embodiment, the SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is administered in combination with the KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, once disease progression has been observed for KRas G12C monotherapy, in which the combination therapy results in enhanced clinical benefit for the patient by increasing OS, PFS, tumor regression, tumor growth inhibition or the duration of stable disease in the patient. In one embodiment, the KRas G12C inhibitor is a compound selected from compound Nos. 1-678 (as numbered in WO2019099524), or a pharmaceutically acceptable salt thereof (e.g., Example No. 234, 359, 478 or 507 or a pharmaceutically acceptable salt thereof).
[00124] In one embodiment, the SOS1 inhibitor is selected from (R)-2-methyl-3-(l-((4- methyl-7-morpholinopyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile, 3-((R)-l-((7-((S)- hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8( lH)-yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 - yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)- 4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(l-((4- methyl-7-(4-methylpiperazin-l-yl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile, (R)-3- ( 1 -((7-(4-ethylpiperazin- 1 -yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile, (R)-2-methyl-3-(l-((4-methyl-7-(piperazin-l-yl)pyrido[3,4-d]pyridazin-l- yl)amino)ethyl)benzonitrile, 3-((R)-l-((7-((S)-3-(dimethylamino)pyrrolidin-l-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (i?)-3-(l-((6-fluoro-4- methyl-7-(4-methylpiperazin-l-yl)phthalazin-l-yl)amino)ethyl)-2-methylbenzonitrile, or a pharmaceutically acceptable salt thereof. In another embodiment, the SOS1 inhibitor is BI1701963.
[00125] In one embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4- d]pyridazin-l-yl)amino)ethyl)benzonitrile, or a pharmaceutically acceptable salt thereof.
[00126] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and 3-((R)-l-((7-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-
8(lH)-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, or a pharmaceutically acceptable salt thereof.
[00127] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, or a pharmaceutically acceptable salt thereof.
[00128] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-2-methyl-3-(l-((4-methyl-7-(4-methylpiperazin-l- yl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile, or a pharmaceutically acceptable salt thereof.
[00129] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-3-(l-((7-(4-ethylpiperazin-l-yl)-4-methylpyrido[3,4- d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, or a pharmaceutically acceptable salt thereof.
[00130] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and (R)-2-methyl-3-(l-((4-methyl-7-(piperazin-l-yl)pyrido[3,4- d]pyridazin-l-yl)amino)ethyl)benzonitrile, or a pharmaceutically acceptable salt thereof.
[00131] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and 3-((R)-l-((7-((S)-3-(dimethylamino)pyrrolidin-l-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, or a pharmaceutically acceptable salt thereof.
[00132] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and (i?)-3-(l-((6-fluoro-4-methyl-7-(4-methylpiperazin-l- yl)phthalazin-l-yl)amino)ethyl)-2-methylbenzonitrile, or a pharmaceutically acceptable salt thereof.
[00133] In another embodiment, the therapeutic combination comprises therapeutically effective amounts of adagrasib and the SOS1 inhibitor is BI1701963.
[00134] The compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, colorectal, pancreas, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compositions and methods of the invention include, but are not limited to, tumor types such as astrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma,
retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In certain embodiments, the cancer is non-small cell lung cancer.
[00135] Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12C mutation (e.g., a KRas G12C-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a combination of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, wherein the SO SI inhibitor synergistically increases the sensitivity of the KRas G12C-associated cancer to the KRas G12C inhibitor. In one embodiment, the KRas G12C inhibitor is a compound selected from compound Nos. 1-678 (as numbered in WO2019099524), or a pharmaceutically acceptable salt thereof (e.g., one of Example Nos. 234, 359, 478 or 507 or a pharmaceutically acceptable salt thereof). In one embodiment, the SOS1 inhibitor is selected from: (R)-2-methyl-3-(l-((4- methyl-7-morpholinopyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile, 3-((R)-l-((7-((S)- hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8( lH)-yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 - yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)- 4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (R)-2-methyl-3-(l-((4- methyl-7-(4-methylpiperazin-l-yl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile, (R)-3- ( 1 -((7-(4-ethylpiperazin- 1 -yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 -yl)amino)ethyl)-2-
methylbenzonitrile, (R)-2-methyl-3-(l-((4-methyl-7-(piperazin-l-yl)pyrido[3,4-d]pyridazin-l- yl)amino)ethyl)benzonitrile, 3-((R)-l-((7-((S)-3-(dimethylamino)pyrrolidin-l-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (i?)-3-(l-((6-fluoro-4- methyl-7-(4-methylpiperazin-l-yl)phthalazin-l-yl)amino)ethyl)-2-methylbenzonitrile, or a pharmaceutically acceptable salt thereof; or the SOS1 inhibitor is BI1701963.
[00136] In one embodiment, the therapeutic combination comprises therapeutically effective amounts of (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-l- yl)amino)ethyl)benzonitrile or a pharmaceutically acceptable salt thereof.
[00137] In a further embodiment, the therapeutic combination comprises therapeutically effective amounts of 3-((R)-l-((7-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile or a pharmaceutically acceptable salt thereof.
[00138] In a further embodiment, the therapeutic combination comprises therapeutically effective amounts of (R)-3-(l-((7-(3-(dimethylamino)-3-methylazetidin-l-yl)-4- methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile or a pharmaceutically acceptable salt thereof.
[00139] In a further embodiment, the therapeutic combination comprises therapeutically effective amounts of (R)-2-methyl-3-(l-((4-methyl-7-(4-methylpiperazin-l-yl)pyrido[3,4- d]pyridazin-l-yl)amino)ethyl)benzonitrile or a pharmaceutically acceptable salt thereof.
[00140] In a further embodiment, the therapeutic combination comprises therapeutically effective amounts of (R)-3-(l-((7-(4-ethylpiperazin-l-yl)-4-methylpyrido[3,4-d]pyridazin-l- yl)amino)ethyl)-2-methylbenzonitrile or a pharmaceutically acceptable salt thereof.
[00141] In a further embodiment, the therapeutic combination comprises therapeutically effective amounts of (R)-2-methyl-3-(l-((4-methyl-7-(piperazin-l-yl)pyrido[3,4-d]pyridazin-l- yl)amino)ethyl)benzonitrile or a pharmaceutically acceptable salt thereof.
[00142] In a further embodiment, the therapeutic combination comprises therapeutically effective amounts of 3-((R)-l-((7-((S)-3-(dimethylamino)pyrrolidin-l-yl)-4-methylpyrido[3,4-
d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile or a pharmaceutically acceptable salt thereof.
[00143] In a further embodiment, the therapeutic combination comprises therapeutically effective amounts of (i?)-3-(l-((6-fluoro-4-methyl-7-(4-methylpiperazin-l-yl)phthalazin-l- yl)amino)ethyl)-2-methylbenzonitrile or a pharmaceutically acceptable salt thereof.
[00144] In a further embodiment, the therapeutic combination comprises therapeutically effective amounts of BI1701963.
[00145] In one embodiment, the KRas G12C compound adagrasib is administered as a tablet or capsule during the period of time. In one embodiment, the tablet or capsule formulation of adagrasib comprises on or more of: about 10 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg and about 2000 mg. . In one embodiment, adagrasib is orally administered once a day (QD) on a daily basis during a period of time. In one embodiment adagrasib is orally administered twice a day (BID) on a daily basis during a period of time.
[00146] In one embodiment, the SOS1 compound is orally administered in the amount of about 20 mg to about 500 mg (e.g., about 20 mg to about 480 mg, about 20 mg to about 460 mg, about 20 mg to about 440 mg, about 20 mg to about 420 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 500 mg, about 40 mg to about 480 mg, about 40 mg to about 460 mg, about 40 mg to about 440 mg, about 40 mg to about 420 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 mg to
about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 500 mg, about 60 mg to about 480 mg, about 60 mg to about 460 mg, about 60 mg to about 440 mg, about 60 mg to about 420 mg, about 60 mg to about 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, about 60 mg to about 340 mg, about 60 mg to about 320 mg, about 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 500 mg, about 80 mg to about 480 mg, about 80 mg to about 460 mg, about 80 mg to about 440 mg, about 80 mg to about 420 mg, about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg, about 80 mg to about 100 mg, about 100 mg to about 500 mg, about 100 mg to about 480 mg, about 100 mg to about 460 mg, about 100 mg to about 440 mg, about 100 mg to about 420 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 500 mg, about 120 mg to about 480 mg, about 120 mg to about 460 mg, about 120 mg to about 440 mg, about 120 mg to about 420 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to
about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 500 mg, about 140 mg to about 480 mg, about 140 mg to about 460 mg, about 140 mg to about 440 mg, about 140 mg to about 420 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 500 mg, about 160 mg to about 480 mg, about 160 mg to about 460 mg, about 160 mg to about 440 mg, about 160 mg to about 420 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 500 mg, about 180 mg to about 480 mg, about 180 mg to about 460 mg, about 180 mg to about 440 mg, about 180 mg to about 420 mg, about 180 mg to about 400 mg, about 180 mg to about 380 mg, about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 500 mg, about 200 mg to about 480 mg, about 200 mg to about 460 mg, about 200 mg to about 440 mg, about 200 mg to about 420 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 500 mg, about 220 mg to about 480 mg, about 220 mg to about 460 mg, about 220 mg to about 440 mg, about 220 mg to about 420 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 500 mg, about 240 mg to about 480 mg, about 240 mg to about 460 mg, about 240 mg to about 440 mg, about 240 mg to about 420 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to
about 280 mg, about 240 mg to about 260 mg, about 260 mg to about 500 mg, about 260 mg to about 480 mg, about 260 mg to about 460 mg, about 260 mg to about 440 mg, about 260 mg to about 420 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 500 mg, about 280 mg to about 480 mg, about 280 mg to about 460 mg, about 280 mg to about 440 mg, about 280 mg to about 420 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 500 mg, about 300 mg to about 480 mg, about 300 mg to about 460 mg, about 300 mg to about 440 mg, about 300 mg to about 420 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 500 mg, about 320 mg to about 480 mg, about 320 mg to about 460 mg, about 320 mg to about 440 mg, about 320 mg to about 420 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 320 mg to about 340 mg, about 340 mg to about 500 mg, about 340 mg to about 480 mg, about 340 mg to about 460 mg, about 340 mg to about 440 mg, about 340 mg to about 420 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 500 mg, about 360 mg to about 480 mg, about 360 mg to about 460 mg, about 360 mg to about 440 mg, about 360 mg to about 420 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 500 mg, about 380 mg to about 480 mg, about 380 mg to about 460 mg, about 380 mg to about 440 mg, about 380 mg to about 420 mg, about 380 mg to about 400 mg, about 400 mg to about 500 mg, about 400 mg to about 480 mg, about 400 mg to about 460 mg, about 400 mg to about 440 mg, about 400 mg to about 420 mg, about 420 mg to about 500 mg, about 420 mg to about 480 mg, about 420 mg to about 460 mg, about 420 mg to about 440 mg, about 440 mg to about 500 mg, about 440 mg to about 480 mg, about 440 mg to about 460 mg, about 460 mg to about 500 mg, about 460 mg to about 480 mg, about 480 mg to about 500 mg, about 25, about 50, about 75, about 100, about 150, about 200, about 250, about 300, about 350, about 400, about 450, or about 500 mg), is administered over a period of time. In one embodiment, the SOS1 compound is orally administered twice a day (BID) on a daily basis during a period of time. In one embodiment adagrasib is orally administered twice a day (BID) on a daily basis during a period of time.
[00147] In one embodiment, the combination therapy comprises oral administration of adagrasib once or twice a day on a daily basis (during a period of time), e.g., in an amount of about 10 mg to about 400 mg (e.g., about 10 mg to about 380 mg, about 10 mg to about 360 mg, about 10 mg to about 340 mg, about 10 mg to about 320 mg, about 10 mg to about 300 mg, about 10 mg to about 280 mg, about 10 mg to about 260 mg, about 10 mg to about 240 mg, about 10 mg to about 220 mg, about 10 mg to about 200 mg, about 10 mg to about 180 mg, about 10 mg to about 160 mg, about 10 mg to about 140 mg, about 10 mg to about 120 mg, about 10 mg to about 100 mg, about 10 mg to about 80 mg, about 10 mg to about 60 mg, about 10 mg to about 40 mg, about 10 mg to about 20 mg, about 20 mg to about 400 mg, about 20 mg to about 380 mg, about 20 mg to about 360 mg, about 20 mg to about 340 mg, about 20 mg to about 320 mg, about 20 mg to about 300 mg, about 20 mg to about 280 mg, about 20 mg to about 260 mg, about 20 mg to about 240 mg, about 20 mg to about 220 mg, about 20 mg to about 200 mg, about 20 mg to about 180 mg, about 20 mg to about 160 mg, about 20 mg to about 140 mg, about 20 mg to about 120 mg, about 20 mg to about 100 mg, about 20 mg to about 80 mg, about 20 mg to about 60 mg, about 20 mg to about 40 mg, about 40 mg to about 400 mg, about 40 mg to about 380 mg, about 40 mg to about 360 mg, about 40 mg to about 340 mg, about 40 mg to about 320 mg, about 40 mg to about 300 mg, about 40 mg to about 280 mg, about 40 mg to about 260 mg, about 40 mg to about 240 mg, about 40 mg to about 220 mg, about 40 mg to about 200 mg, about 40 mg to about 180 mg, about 40 mg to about 160 mg, about 40 mg to about 140 mg, about 40 mg to about 120 mg, about 40 mg to about 100 mg, about 40 mg to about 80 mg, about 40 mg to about 60 mg, about 60 mg to about 400 mg, about 60 mg to about 380 mg, about 60 mg to about 360 mg, about 60 mg to about 340 mg, about 60 mg to about 320 mg, about 60 mg to about 300 mg, about 60 mg to about 280 mg, about 60 mg to about 260 mg, about 60 mg to about 240 mg, about 60 mg to about 220 mg, about 60 mg to about 200 mg, about 60 mg to about 180 mg, about 60 mg to about 160 mg, about 60 mg to about 140 mg, about 60 mg to about 120 mg, about 60 mg to about 100 mg, about 60 mg to about 80 mg, about 80 mg to about 400 mg, about 80 mg to about 380 mg, about 80 mg to about 360 mg, about 80 mg to about 340 mg, about 80 mg to about 320 mg, about 80 mg to about 300 mg, about 80 mg to about 280 mg, about 80 mg to about 260 mg, about 80 mg to about 240 mg, about 80 mg to about 220 mg, about 80 mg to about 200 mg, about 80 mg to about 180 mg, about 80 mg to about 160 mg, about 80 mg to about 140 mg, about 80 mg to about 120 mg,
about 80 mg to about 100 mg, about 100 mg to about 400 mg, about 100 mg to about 380 mg, about 100 mg to about 360 mg, about 100 mg to about 340 mg, about 100 mg to about 320 mg, about 100 mg to about 300 mg, about 100 mg to about 280 mg, about 100 mg to about 260 mg, about 100 mg to about 240 mg, about 100 mg to about 220 mg, about 100 mg to about 200 mg, about 100 mg to about 180 mg, about 100 mg to about 160 mg, about 100 mg to about 140 mg, about 100 mg to about 120 mg, about 120 mg to about 400 mg, about 120 mg to about 380 mg, about 120 mg to about 360 mg, about 120 mg to about 340 mg, about 120 mg to about 320 mg, about 120 mg to about 300 mg, about 120 mg to about 280 mg, about 120 mg to about 260 mg, about 120 mg to about 240 mg, about 120 mg to about 220 mg, about 120 mg to about 200 mg, about 120 mg to about 180 mg, about 120 mg to about 160 mg, about 120 mg to about 140 mg, about 140 mg to about 400 mg, about 140 mg to about 380 mg, about 140 mg to about 360 mg, about 140 mg to about 340 mg, about 140 mg to about 320 mg, about 140 mg to about 300 mg, about 140 mg to about 280 mg, about 140 mg to about 260 mg, about 140 mg to about 240 mg, about 140 mg to about 220 mg, about 140 mg to about 200 mg, about 140 mg to about 180 mg, about 140 mg to about 160 mg, about 160 mg to about 400 mg, about 160 mg to about 380 mg, about 160 mg to about 360 mg, about 160 mg to about 360 mg, about 160 mg to about 340 mg, about 160 mg to about 320 mg, about 160 mg to about 300 mg, about 160 mg to about 280 mg, about 160 mg to about 260 mg, about 160 mg to about 240 mg, about 160 mg to about 220 mg, about 160 mg to about 200 mg, about 160 mg to about 180 mg, about 180 mg to about 400 mg, about 180 mg to about 380 mg, about 180 mg to about 360 mg, about 180 mg to about 340 mg, about 180 mg to about 320 mg, about 180 mg to about 300 mg, about 180 mg to about 280 mg, about 180 mg to about 260 mg, about 180 mg to about 240 mg, about 180 mg to about 220 mg, about 180 mg to about 200 mg, about 200 mg to about 400 mg, about 200 mg to about 380 mg, about 200 mg to about 360 mg, about 200 mg to about 340 mg, about 200 mg to about 320 mg, about 200 mg to about 300 mg, about 200 mg to about 280 mg, about 200 mg to about 260 mg, about 200 mg to about 240 mg, about 200 mg to about 220 mg, about 220 mg to about 400 mg, about 220 mg to about 380 mg, about 220 mg to about 360 mg, about 220 mg to about 340 mg, about 220 mg to about 320 mg, about 220 mg to about 300 mg, about 220 mg to about 280 mg, about 220 mg to about 260 mg, about 220 mg to about 240 mg, about 240 mg to about 400 mg, about 240 mg to about 380 mg, about 240 mg to about 360 mg, about 240 mg to about 340 mg, about 240 mg to about 320 mg, about 240 mg to about 300 mg, about 240 mg to about 280 mg,
about 240 mg to about 260 mg, about 260 mg to about 400 mg, about 260 mg to about 380 mg, about 260 mg to about 360 mg, about 260 mg to about 340 mg, about 260 mg to about 320 mg, about 260 mg to about 300 mg, about 260 mg to about 280 mg, about 280 mg to about 400 mg, about 280 mg to about 380 mg, about 280 mg to about 360 mg, about 280 mg to about 340 mg, about 280 mg to about 320 mg, about 280 mg to about 300 mg, about 300 mg to about 400 mg, about 300 mg to about 380 mg, about 300 mg to about 360 mg, about 300 mg to about 340 mg, about 300 mg to about 320 mg, about 320 mg to about 400 mg, about 320 mg to about 380 mg, about 320 mg to about 360 mg, about 340 mg to about 360 mg, about 340 mg to about 400 mg, about 340 mg to about 380 mg, about 340 mg to about 360 mg, about 360 mg to about 400 mg, about 360 mg to about 380 mg, about 380 mg to about 400 mg, about 100 mg, about 200 mg, about 300 mg, or about 400 mg), and oral administration of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof which is administered, for example once a day on a daily basis (during a period of time). In one embodiment, the KRas G12C inhibitor adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof is orally administered once daily. In another embodiment, the KRas G12C inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, is orally administered twice daily.
[00148] One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and/or animal models are predictive of the ability of a test compound of the combination or the combination to treat or prevent a given disorder.
[00149] One skilled in the art will further recognize that human clinical trials including first-in-human, dose ranging and efficacy trials, in healthy patients and/or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts.
SYNERGY
[00150] In one embodiment, the addition of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, synergistically increases the activity of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof against cancer or cancer cell lines expressing KRas G12C.
Any method for determining whether two compounds exhibit synergy may be used for determining the synergistic effect of the combination.
[00151] Several mathematical models have been developed to determine whether two compounds act synergistically, i.e., beyond a mere additive effect. For instance, Loewe Additivity (Loewe (1928) Physiol. 27: 47-187), Bliss Independence (Bliss (1939) Ann. Appl. Biol. 26: 585-615), Highest Single Agent, ZIP (Yadav et al (2015) Comput Struct Biotech J 13: 504-513) and other models (Chou & Talalay (1984) Adv Enzyme Regul 22: 27-55. #6382953; and Greco et al. (1995) Pharmacol Rev 47(2): 331-85. #7568331) are well known models in the pharmaceutical industry and may be used to calculate a “synergy score” that indicates whether synergy was detected and the magnitude of such synergy. Combining these synergy scores produces a composite synergy score which may be used to evaluate and characterize the KRas G12C inhibitor compound adagrasib-B in combination with a SOS1 inhibitor.
[00152] In general, the mathematical models use data obtained from single agent values to determine the predicted additive effect of the combination which is compared to the observed effect for the combination. If the observed effect is greater than the predicted effect, the combination is deemed to be synergistic. For example, the Bliss independence model compares the observed combination response (Fo) with the predicted combination response (FP), which was obtained based on the assumption that there is no effect from drug-drug interactions. Typically, the combination effect is declared synergistic if Yo is greater than Yp.
[00153] In some embodiments, “synergistic effect” as used herein refers to combination of a KRasKRas inhibitor or a pharmaceutically acceptable salt thereof, and a SOS 1 SOS 1 inhibitor or a pharmaceutically acceptable salt thereof producing an effect, for example, any of the beneficial or desired results including clinical results or endpoints as described herein, which is greater than the sum of the effect observed when a compound such as one described in compound Nos. 1-678 as numbered in WO2019099524, for instance adagrasib, and a SOS1 inhibitor or a pharmaceutically acceptable salt thereof are administered alone. In one embodiment, the KRas G12C inhibitor is adagrasib (MRTX-849, Example No. 478 in WO20 19099524) or a pharmaceutically acceptable salt thereof). In one embodiment, the SOS1 inhibitor is selected from (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-l- yl)amino)ethyl)benzonitrile, 3-((R)-l-((7-((S)-hexahydropyrazino[2,l-c][l,4]oxazin-8(lH)-yl)-4-
methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile, (R)-3-(l-((7-(3- (dimethylamino)-3-methylazetidin-l-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2- methylbenzonitrile, (R)-2-methyl-3-(l-((4-methyl-7-(4-methylpiperazin-l-yl)pyrido[3,4- d]pyridazin-l-yl)amino)ethyl)benzonitrile, (R)-3-(l-((6-fluoro-4-methyl-7-(4-methylpiperazin-l- yl)phthalazin-l-yl)amino)ethyl)-2-methylbenzonitrile, or a pharmaceutically acceptable salt thereof, or a SOS1 inhibitor such as BI1701963.
[00154] In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of (R)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4- d]pyridazin-l-yl)amino)ethyl)benzonitrile and adagrasib . In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of 3-((R)-l-((7-((S)- hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8( lH)-yl)-4-methylpyrido[3 ,4-d]pyridazin- 1 - yl)amino)ethyl)-2-methylbenzonitrile and adagrasib. In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of (R)-3-(l-((7-(3- (dimethylamino)-3-methylazetidin-l-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2- methylbenzonitrile and adagrasib. In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of (R)-2-methyl-3-(l-((4-methyl-7-(4- methylpiperazin-l-yl)pyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile and adagrasib. In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of (7?)-3-(l-((7-(4-ethylpiperazin-l-yl)-4-methylpyrido[3,4-<i]pyridazin-l- yl)amino)ethyl)-2-methylbenzonitrile, and adagrasib. In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of (f?)-2-methyl-3-(l-((4- methyl-7-(piperazin-l-yl)pyrido[3,4-i/]pyridazin-l-yl)amino)ethyl)benzonitrile, and adagrasib.
In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of 3-((i?)-l-((7-((ri)-3-(dimethylamino)pyrrolidin-l-yl)-4-methylpyrido[3,4-<i]pyridazin- l-yl)amino)ethyl)-2-methylbenzonitrile, and adagrasib. In one embodiment, the synergistic therapeutic combination comprises therapeutically effective amounts of (i?)-3-(l-((6-fluoro-4- methyl-7-(4-methylpiperazin-l-yl)phthalazin-l-yl)amino)ethyl)-2-methylbenzonitrile and adagrasib.
[00155] In one embodiment, the therapeutic combination comprises therapeutically effective amounts of BI 1701963 and adagrasib.
[00156] In some embodiments, the methods provided herein can result in a 1% to 99% (e.g., 1% to 98%, 1% to 95%, 1% to 90%, 1 to 85%, 1 to 80%, 1% to 75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 2% to 99%, 2% to 90%, 2% to 85%, 2% to 80%, 2% to 75%, 2% to 70%, 2% to 65%, 2% to 60%, 2% to 55%, 2% to 50%, 2% to 45%, 2% to 40%, 2% to 35%, 2% to 30%, 2% to 25%, 2% to 20%, 2% to 15%, 2% to 10%, 2% to 5%, 4% to 99%, 4% to 95%, 4% to 90%, 4% to 85%, 4% to 80%, 4% to 75%, 4% to 70%, 4% to 65%, 4% to 60%, 4% to 55%, 4% to 50%, 4% to 45%, 4% to 40%, 4% to 35%, 4% to 30%, 4% to 25%, 4% to 20%, 4% to 15%, 4% to 10%, 6% to 99%, 6% to 95%, 6% to 90%, 6% to 85%, 6% to 80%, 6% to 75%, 6% to 70%, 6% to 65%, 6% to 60%, 6% to 55%, 6% to 50%, 6% to 45%, 6% to 40%, 6% to 35%, 6% to 30%, 6% to 25%, 6% to 20%, 6% to 15%, 6% to 10%, 8% to 99%, 8% to 95%, 8% to 90%, 8% to 85%, 8% to 80%, 8% to 75%, 8% to 70%, 8% to 65%, 8% to 60%, 8% to 55%, 8% to 50%, 8% to 45%, 8% to 40%, 8% to 35%, 8% to 30%, 8% to 25%, 8% to 20%, 8% to 15%, 10% to 99%, 10% to 95%, 10% to 90%, 10% to 85%, 10% to 80%, 10% to 75%, 10% to 70%, 10% to 65%, 10% to 60%, 10% to 55%, 10% to 50%, 10% to 45%, 10% to 40%, 10% to 35%, 10% to 30%, 10% to 25%, 10% to 20%, 10% to 15%, 15% to 99%, 15% to 95%, 15% to 90%, 15% to 85%, 15% to 80%, 15% to 75%, 15% to 70%, 15% to 65%, 15% to 60%, 15% to 55%, 15% to 50%, 15% to 55%, 15% to 50%, 15% to 45%, 15% to 40%, 15% to 35%, 15% to 30%, 15% to 25%, 15% to 20%, 20% to 99%, 20% to 95%, 20% to 90%, 20% to 85%, 20% to 80%, 20% to 75%, 20% to 70%, 20% to 65%, 20% to 60%, 20% to 55%, 20% to 50%, 20% to 45%, 20% to 40%, 20% to 35%, 20% to 30%, 20% to 25%, 25% to 99%, 25% to 95%, 25% to 90%, 25% to 85%, 25% to 80%, 25% to 75%, 25% to 70%, 25% to 65%, 25% to 60%, 25% to 55%, 25% to 50%, 25% to 45%, 25% to 40%, 25% to 35%, 25% to 30%, 30% to 99%, 30% to 95%, 30% to 90%, 30% to 85%, 30% to 80%, 30% to 75%, 30% to 70%, 30% to 65%, 30% to 60%, 30% to 55%, 30% to 50%, 30% to 45%, 30% to 40%, 30% to 35%, 35% to 99%, 35% to 95%, 35% to 90%, 35% to 85%, 35% to 80%, 35% to 75%, 35% to 70%, 35% to 65%, 35% to 60%, 35% to 55%, 35% to 50%, 35% to 45%, 35% to 40%, 40% to 99%, 40% to 95%, 40% to 90%, 40% to 85%, 40% to 80%, 40% to 75%, 40% to 70%, 40% to 65%, 40% to 60%, 40% to 55%, 40% to 60%, 40% to 55%, 40% to 50%, 40% to 45%, 45% to 99%, 45% to 95%, 45% to 95%, 45% to 90%, 45% to 85%, 45% to 80%, 45% to 75%, 45% to 70%, 45% to 65%, 45% to 60%, 45% to 55%, 45% to 50%, 50% to 99%, 50% to 95%, 50% to
90%, 50% to 85%, 50% to 80%, 50% to 75%, 50% to 70%, 50% to 65%, 50% to 60%, 50% to 55%, 55% to 99%, 55% to 95%, 55% to 90%, 55% to 85%, 55% to 80%, 55% to 75%, 55% to 70%, 55% to 65%, 55% to 60%, 60% to 99%, 60% to 95%, 60% to 90%, 60% to 85%, 60% to 80%, 60% to 75%, 60% to 70%, 60% to 65%, 65% to 99%, 60% to 95%, 60% to 90%, 60% to 85%, 60% to 80%, 60% to 75%, 60% to 70%, 60% to 65%, 70% to 99%, 70% to 95%, 70% to 90%, 70% to 85%, 70% to 80%, 70% to 75%, 75% to 99%, 75% to 95%, 75% to 90%, 75% to 85%, 75% to 80%, 80% to 99%, 80% to 95%, 80% to 90%, 80% to 85%, 85% to 99%, 85% to 95%, 85% to 90%, 90% to 99%, 90% to 95%, or 95% to 100%) reduction in the volume of one or more solid tumors in a patient following treatment with the combination therapy for a period of time between 1 day and 2 years (e.g., between 1 day and 22 months, between 1 day and 20 months, between 1 day and 18 months, between 1 day and 16 months, between 1 day and 14 months, between 1 day and 12 months, between 1 day and 10 months, between 1 day and 9 months, between 1 day and 8 months, between 1 day and 7 months, between 1 day and 6 months, between 1 day and 5 months, between 1 day and 4 months, between 1 day and 3 months, between 1 day and 2 months, between 1 day and 1 month, between one week and 2 years, between 1 week and 22 months, between 1 week and 20 months, between 1 week and 18 months, between 1 week and 16 months, between 1 week and 14 months, between 1 week and 12 months, between 1 week and 10 months, between 1 week and 9 months, between 1 week and 8 months, between 1 week and 7 months, between 1 week and 6 months, between 1 week and 5 months, between 1 week and 4 months, between 1 week and 3 months, between 1 week and 2 months, between 1 week and 1 month, between 2 weeks and 2 years, between 2 weeks and 22 months, between 2 weeks and 20 months, between 2 weeks and 18 months, between 2 weeks and 16 months, between 2 weeks and 14 months, between 2 weeks and 12 months, between 2 weeks and 10 months, between 2 weeks and 9 months, between 2 weeks and 8 months, between 2 weeks and 7 months, between 2 weeks and 6 months, between 2 weeks and 5 months, between 2 weeks and 4 months, between 2 weeks and 3 months, between 2 weeks and 2 months, between 2 weeks and 1 month, between 1 month and 2 years, between 1 month and 22 months, between 1 month and 20 months, between 1 month and 18 months, between 1 month and 16 months, between 1 month and 14 months, between 1 month and 12 months, between 1 month and 10 months, between 1 month and 9 months, between 1 month and 8 months, between 1 month and 7 months, between 1 month and 6 months, between 1 month and 6 months, between 1 month and 5
months, between 1 month and 4 months, between 1 month and 3 months, between 1 month and 2 months, between 2 months and 2 years, between 2 months and 22 months, between 2 months and 20 months, between 2 months and 18 months, between 2 months and 16 months, between 2 months and 14 months, between 2 months and 12 months, between 2 months and 10 months, between 2 months and 9 months, between 2 months and 8 months, between 2 months and 7 months, between 2 months and 6 months, or between 2 months and 5 months, between 2 months and 4 months, between 3 months and 2 years, between 3 months and 22 months, between 3 months and 20 months, between 3 months and 18 months, between 3 months and 16 months, between 3 months and 14 months, between 3 months and 12 months, between 3 months and 10 months, between 3 months and 8 months, between 3 months and 6 months, between 4 months and 2 years, between 4 months and 22 months, between 4 months and 20 months, between 4 months and 18 months, between 4 months and 16 months, between 4 months and 14 months, between 4 months and 12 months, between 4 months and 10 months, between 4 months and 8 months, between 4 months and 6 months, between 6 months and 2 years, between 6 months and 22 months, between 6 months and 20 months, between 6 months and 18 months, between 6 months and 16 months, between 6 months and 14 months, between 6 months and 12 months, between 6 months and 10 months, or between 6 months and 8 months) (e.g., as compared to the size of the one or more solid tumors in the patient prior to treatment).
[00157] The phrase “time of survival” means the length of time between the identification or diagnosis of cancer (e.g., any of the cancers described herein) in a mammal by a medical professional and the time of death of the mammal (caused by the cancer). Methods of increasing the time of survival in a mammal having a cancer are described herein.
[00158] In some embodiments, any of the methods described herein can result in an increase (e.g., a 1% to 400%, 1% to 380%, 1% to 360%, 1% to 340%, 1% to 320%, 1% to 300%, 1% to 280%, 1% to 260%, 1% to 240%, 1% to 220%, 1% to 200%, 1% to 180%, 1% to 160%,
1% to 140%, 1% to 120%, 1% to 100%, 1% to 95%, 1% to 90%, 1% to 85%, 1% to 80%, 1% to
75%, 1% to 70%, 1% to 65%, 1% to 60%, 1% to 55%, 1% to 50%, 1% to 45%, 1% to 40%, 1% to 35%, 1% to 30%, 1% to 25%, 1% to 20%, 1% to 15%, 1% to 10%, 1% to 5%, 5% to 400%, 5% to 380%, 5% to 360%, 5% to 340%, 5% to 320%, 5% to 300%, 5% to 280%, 5% to 260%,
5% to 240%, 5% to 220%, 5% to 200%, 5% to 180%, 5% to 160%, 5% to 140%, 5% to 120%,
% to 100%, 5% to 90%, 5% to 80%, 5% to 70%, 5% to 60%, 5% to 50%, 5% to 40%, 5% to0%, 5% to 20%, 5% to 10%, 10% to 400%, 10% to 380%, 10% to 360%, 10% to 340%, 10% to20%, 10% to 300%, 10% to 280%, 10% to 260%, 10% to 240%, 10% to 220%, 10% to 200%,0% to 180%, 10% to 160%, 10% to 140%, 10% to 120%, 10% to 100%, 10% to 90%, 10% to0%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 20% to00%, 20% to 380%, 20% to 360%, 20% to 340%, 20% to 320%, 20% to 300%, 20% to 280%,0% to 260%, 20% to 240%, 20% to 220%, 20% to 200%, 20% to 180%, 20% to 160%, 20% to40%, 20% to 120%, 20% to 100%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% 50%, 20% to 40%, 20% to 30%, 30% to 400%, 30% to 380%, 30% to 360%, 30% to 340%,0% to 320%, 30% to 300%, 30% to 280%, 30% to 260%, 30% to 240%, 30% to 220%, 30% to00%, 30% to 180%, 30% to 160%, 30% to 140%, 30% to 120%, 30% to 100%, 30% to 90%,0% to 80%, 30% to 70%, 30% to 60%, 30% to 50%, 30% to 40%, 40% to 400%, 40% to 380%,0% to 360%, 40% to 340%, 40% to 320%, 40% to 300%, 40% to 280%, 40% to 260%, 40% to40%, 40% to 220%, 40% to 200%, 40% to 180%, 40% to 160%, 40% to 140%, 40% to 120%,0% to 100%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to 50%, 50% to 400%,0% to 380%, 50% to 360%, 50% to 340%, 50% to 320%, 50% to 300%, 50% to 280%, 50% to60%, 50% to 240%, 50% to 220%, 50% to 200%, 50% to 180%, 50% to 160%, 50% to 140%,0% to 140%, 50% to 120%, 50% to 100%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to0%, 60% to 400%, 60% to 380%, 60% to 360%, 60% to 340%, 60% to 320%, 60% to 300%,0% to 280%, 60% to 260%, 60% to 240%, 60% to 220%, 60% to 200%, 60% to 180%, 60% to60%, 60% to 140%, 60% to 120%, 60% to 100%, 60% to 90%, 60% to 80%, 60% to 70%, 70% 400%, 70% to 380%, 70% to 360%, 70% to 340%, 70% to 320%, 70% to 300%, 70% to80%, 70% to 260%, 70% to 240%, 70% to 220%, 70% to 200%, 70% to 180%, 70% to 160%,0% to 140%, 70% to 120%, to 100%, 70% to 90%, 70% to 80%, 80% to 400%, 80% to 380%,0% to 360%, 80% to 340%, 80% to 320%, 80% to 300%, 80% to 280%, 80% to 260%, 80% to40%, 80% to 220%, 80% to 200%, 80% to 180%, 80% to 160%, 80% to 140%, 80% to 120%,0% to 100%, 80% to 90%, 90% to 400%, 90% to 380%, 90% to 360%, 90% to 340%, 90% to20%, 90% to 300%, 90% to 280%, 90% to 260%, 90% to 240%, 90% to 220%, 90% to 200%,0% to 180%, 90% to 160%, 90% to 140%, 90% to 120%, 90% to 100%, 100% to 400%, 100% 380%, 100% to 360%, 100% to 340%, 100% to 320%, 100% to 300%, 100% to 280%, 100% 260%, 100% to 240%, 100% to 220%, 100% to 200%, 100% to 180%, 100% to 160%, 100%
to 140%, 100% to 120%, 120% to 400%, 120% to 380%, 120% to 360%, 120% to 340%, 120% to 320%, 120% to 300%, 120% to 280%, 120% to 260%, 120% to 240%, 120% to 220%, 120% to 200%, 120% to 180%, 120% to 160%, 120% to 140%, 140% to 400%, 140% to 380%, 140% to 360%, 140% to 340%, 140% to 320%, 140% to 300%, 140% to 280%, 140% to 260%, 140% to 240%, 140% to 220%, 140% to 200%, 140% to 180%, 140% to 160%, 160% to 400%, 160% to 380%, 160% to 360%, 160% to 340%, 160% to 320%, 160% to 300%, 160% to 280%, 160% to 260%, 160% to 240%, 160% to 220%, 160% to 200%, 160% to 180%, 180% to 400%, 180% to 380%, 180% to 360%, 180% to 340%, 180% to 320%, 180% to 300%, 180% to 280%, 180% to 260%, 180% to 240%, 180% to 220%, 180% to 200%, 200% to 400%, 200% to 380%, 200% to 360%, 200% to 340%, 200% to 320%, 200% to 300%, 200% to 280%, 200% to 260%, 200% to 240%, 200% to 220%, 220% to 400%, 220% to 380%, 220% to 360%, 220% to 340%, 220% to 320%, 220% to 300%, 220% to 280%, 220% to 260%, 220% to 240%, 240% to 400%, 240% to 380%, 240% to 360%, 240% to 340%, 240% to 320%, 240% to 300%, 240% to 280%, 240% to 260%, 260% to 400%, 260% to 380%, 260% to 360%, 260% to 340%, 260% to 320%, 260% to 300%, 260% to 280%, 280% to 400%, 280% to 380%, 280% to 360%, 280% to 340%, 280% to 320%, 280% to 300%, 300% to 400%, 300% to 380%, 300% to 360%, 300% to 340%, or 300% to 320%) in the time of survival of the patient (e.g., as compared to a patient having a similar cancer and administered a different treatment or not receiving a treatment).
[00159] In some embodiments of any of the methods described herein, before treatment with the compositions or methods of the invention, the patient was treated with one or more of a chemotherapy, a targeted anticancer agent, radiation therapy, and surgery, and optionally, the prior treatment was unsuccessful; and/or the patient has been administered surgery and optionally, the surgery was unsuccessful; and/or the patient has been treated with a platinum- based chemotherapeutic agent, and optionally, the patient has been previously determined to be non-responsive to treatment with the platinum-based chemotherapeutic agent; and/or the patient has been treated with a kinase inhibitor, and optionally, the prior treatment with the kinase inhibitor was unsuccessful; and/or the patient was treated with one or more other therapeutic agent(s).
KITS
[00160] The present invention also relates to a kit comprising a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof. Also provided is a kit comprising a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, for use in treating a hematological cancer.
[00161] In a related aspect, the invention provides a kit containing a dose of a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and dose of the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, in an amount effective to inhibit proliferation of cancer cells, particularly KRas G12C-expressing cancer cells, in a subject. The kit in some cases includes an insert with instructions for administration of the a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, and the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof,. The insert may provide a user with one set of instructions for using the a SOS1 inhibitor, or a pharmaceutically acceptable salt or a pharmaceutical composition thereof, in combination with the KRas G12C inhibitor compound adagrasib or a pharmaceutically acceptable salt or a pharmaceutical composition thereof.
[00162] The following Examples are intended to illustrate further certain embodiments of the invention and are not intended to limit the scope of the invention.
EXAMPLE A
In Vivo Models for Examining KRas G12C inhibitor - SOS1 Inhibitor Combinations
[00163] Immunocompromised nude/nude mice are inoculated in the right hind flank with cells or patient derived tumor samples harboring a KRas G12C mutation. When tumor volumes reach between 200 - 400 mm3 in size, the mice are divided into four groups of 4-12 mice each. The first group is administered vehicle only. The second group is administered a single agent dose of the KRas G12C inhibitor at a concentration that yields a maximal biological effect or a less than maximal biological effect, depending on the cell line and the single agent activity, that
does not result in complete tumor regression. The third group is administered a single agent dose of the SOS1 inhibitor at a concentration that yields a maximal biological effect or a less than maximal biological effect, depending on the cell line and the single agent activity, that also does not result in complete tumor regression. An optional group is administered with a single agent dose of the MEK inhibitor (VS-6766) that yields less than maximal biological effect. The final group is administered the single agent dose of the KRas G12C inhibitor in combination with the single agent dose of the SO SI inhibitor or with single agent dose of the KRas G12C inhibitor in combination with the single agent dose of the SOS1 inhibitor and the single agent VS-6766. The treatment period varies from cell line to cell line but typically is between 20-42 days. Tumor volumes are measured using a caliper every two - three days and tumor volumes are calculated by the formula: 0.5 x (Length x Width)2. A greater degree of tumor growth inhibition for the combination in this model demonstrates that the combination therapy is likely to have a clinically meaningful benefit to treated subjects relative to treatment with only a KRas G12C inhibitor.
[00164] 16 - 32 nude/nude, Balb/c nude, or NOD/SCID mice per study were inoculated in the right hind limb with 5 x 106 of the indicated cell line or tumor fragment. When tumor volume reached -200 - 400 mm3 (Study Day 0), 4 or more mice in each of the four to six groups were administered p.o. daily for 20-42 days: vehicle only (0.5% MC (4000cps)/0.2% Tween80 in water), 10, 30, or 100 mg/kg of KRas G12C inhibitor adagrasib (10% Captisol in 50 mM citrate buffer, pH 5.0), 0.3 mg/kg of the MEK inhibitor VS-6766 (5% DMSO with 10% Hydroxypropyl-P-cyclodextrin in water), 50 or 100 mg/kg of the SOS1 inhibitor (R)-2-methyl-3- (l-((4-methyl-7-morpholinopyrido[3,4-d]pyridazin-l-yl)amino)ethyl)benzonitrile (MRTX-0902) (0.5% MC (4000cps)/0.2% Tween80 in water), 3-((R)-l-((7-((S)-hexahydropyrazino[2,l- c][l,4]oxazin-8(lH)-yl)-4-methylpyrido[3,4-d]pyridazin-l-yl)amino)ethyl)-2-methylbenzonitrile (MRTX-2006) (20% SBE-p-CD / 50 mM citric acid pH 5), or (R)-2-methyl-3-(l-((4-methyl-7- (4-methylpiperazin- 1 -yl)pyrido[3 ,4-d]pyridazin- 1 -yl)amino)ethyl)benzonitrile (MRTX-4197) (20% SBE-P-CD / 50 mM citric acid pH 5), or 10, 30, or 100 mg/kg of KRas G12C inhibitor adagrasib and 50 or 100 mg/kg of MRTX-0902, MRTX-2006, or MRTX-4197. An additional combination group with 0.3 mg/kg MEK inhibitor VS-6766 was included for the triple combination study. Tumor volumes, measured at pre-specified days, for the 4-8 mice per group were averaged and are reported for MIA PaCa-2 cells in Tables 1, 2, 3 and 4; LU99 cells in
Table 5; NCI-H2122 cells in Tables 6 and 7; CR6256 colorectal patient-derived tumors in Table 8
Table 1
Average Tumor Volumes (mm3) of MIA PaCA-2 Tumor Bearing Mice Treated with Single
Agents and in Combination
[00165] As shown in Figure 1 and Table 1, the administration of adagrasib or MRTX- 0902 as a single agent exhibited 76.3% and 37.5% tumor growth at Day 27, respectively. The combination of the SOS1 inhibitor MRTX-0902 and adagrasib resulted in -73.4% tumor regression at Day 27.
Table 2
Average Tumor Volumes (mm3) of MIA PaCA-2 Tumor Bearing Mice Treated with Single
Agents and in Combination
[00166] As shown in Figure 2 and Table 2, the administration of single agent adagrasib or 25 and 50 mg/kg BID MRTX-0902 exhibited 93.5%, 41.2% , and 52.9% tumor growth at Day 25, respectively. The combinations of the SOS1 inhibitor MRTX-0902 (25 and 50 mg/kg BID) and adagrasib resulted in -54.1 and -92.1% tumor regression, respectively, at Day 25.
Table 3
Average Tumor Volumes (mm3) of MIA PaCA-2 Tumor Bearing Mice Treated with Single
Agents and in Combination
[00167] As shown in Figure 3 and Table 3, the administration of adagrasib or MRTX- 2006 as a single agent exhibited 77.4% and 29.7% tumor growth at Day 27, respectively. The combination of the SOS1 inhibitor MRTX-2006 and adagrasib resulted in 96.0% tumor growth inhibition at Day 27.
Table 4
Average Tumor Volumes (mm3) of MIA PaCA-2 Tumor Bearing Mice Treated with Single
Agents and in Combination
[00168] As shown in Figure 4 and Table 4, the administration of adagrasib or MRTX- 4197 as a single agent exhibited 89.2% and 78.0% tumor growth at Day 20, respectively. The combination of the SOS1 inhibitor MRTX-4197 and adagrasib resulted in -73.0% tumor regression at Day 28.
Table 5
Average Tumor Volumes (mm3) of LU99 Tumor Bearing Mice Treated with Single Agents and in Combination
[00169] As shown in Figure 5 and Table 5, the administration of adagrasib or MRTX- 0902 as a single agent exhibited 98.6% and 21.4% tumor growth at Day 28, respectively. The combination of the SOS1 inhibitor MRTX-0902 and adagrasib resulted in -90.9% tumor regression at Day 26.
Table 6
Average Tumor Volumes (mm3) of H2122 Tumor Bearing Mice Treated with Single Agents and in Combination
[00170] As shown in Figure 6 and Table 6, the administration of adagrasib or MRTX- 0902 as a single agent exhibited 86.3% and 9.2% tumor growth at Day 28, respectively. The combination of the SOS1 inhibitor MRTX-0902 and adagrasib resulted in 95.4% tumor growth inhibition at Day 20.
Table 7
Average Tumor Volumes (mm3) of H2122 Tumor Bearing Mice Treated with Single Agents and in Combination
[00171] As shown in Fighure 7 and Table 7, the administration of adagrasib, MRTX-0902, or VS-6766 as a single agent exhibited 86.9%, 13.7%, and 81.1% tumor growth at Day 23, respectively. The combination of the SOS1 inhibitor MRTX-0902, VS-6766, and adagrasib resulted in -61.9% regression at Day 23.
Table 8
Average Tumor Volumes (mm3) of CR6256 Tumor Bearing Mice Treated with Single Agents and in Combination
[00172] As shown in Figure 8 and Table 8, the administration of adagrasib or MRTX- 0902 as a single agent exhibited 99.0% and 6.1% tumor growth at Day 42, respectively. The combination of the SOS1 inhibitor MRTX-0902 and adagrasib resulted in -80.4% regression at Day 42.
[00173] As shown in Figure 9, the administration of MRTX-0902 with adagrasib leads to broad antitumor activity in KRASG12C-mutant human tumor cell line-derived and patient- derived xenograft models from pancreatic, non-small cell lung, colorectal, and esophageal cancer. These results demonstrate that the combination therapy resulted in greater amount of
tumor growth inhibition compared to either single agent alone demonstrating enhanced in vivo anti -tumor efficacy of the combination against KRas G12C expressing cancer.
[00174] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth, and as follows in the scope of the appended claims.
Claims
1. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of the KRas G12C inhibitor adagrasib: or a pharmaceutically acceptable salt thereof, and a SOS1 inhibitor.
2. The method according to claim 1, wherein the SOS1 inhibitor is selected from:
Me SVSe
(f?)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4-<i]pyridazin-l- yl)amino)ethyl)benzonitrile,
Me Me
3 -(( R )- 1 -((7-((ri)-hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(li7)-yl)-4-methylpyrido[3 ,4- djpyridazin- 1 -yl)amino)ethyl)-2-methylbenzonitrile,
(R)-3-( \ -((7-(3 -(dim ethyl ami no)-3 -methyl azetidin- 1 -yl)-4-methylpyrido[3,4-i/]pyridazin- 1 - yl)amino)ethyl)-2-methylbenzonitrile, and e a vse
(i?)-2-methyl-3-(l-((4-methyl-7-(4-methylpiperazin-l-yl)pyrido[3,4-<i]pyridazin-l- yl)amino)ethyl)benzonitrile, e
(i?)-3-( 1 -((7-(4-ethylpiperazin- 1 -yl)-4-mcthylpyrido| 3.4-£/|pyridazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile,
Me Me
(//)-2-mcthyl-3-( 1 -((4-methyl-7-(piperazin- 1 -yl)pyrido[3,4-ri]pyridazin- 1 -yl)amino)ethyl)benzonitrile, and
Me Me
3 -((//)- 1 -((7 -((.Y)-3 -(dimethylamino)pyrrolidin- 1 -yl)-4-methylpyrido [3 ,4-riJpyridazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile, and
Me Me
(R)- 3 -( 1 -((6-fluoro-4-methyl-7-(4-methylpiperazin- 1 -yl)phthalazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile, and pharmaceutically acceptable salts thereof.
3. The method according to claim 1, wherein the SO SI inhibitor is
Me Me
M® or a pharmaceutically acceptable salt thereof.
4. The method according to claim 3, wherein the method also comprises administering to the subject in need thereof a compound with the following structure:
acceptable salt thereof.
5. A method of treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a combination of:
-the KRas G12C inhibitor adagrasib:
or a pharmaceutically acceptable salt thereof,
-a SOS1 inhibitor:
pharmaceutically acceptable salt thereof, and
- a MEK inhibitor:
, or a pharmaceutically acceptable salt thereof.
6 The method according to claim 1, wherein the SOS1 inhibitor compound is BI1701963.
7. The method according to any one of claims 1-6, wherein the SOS1 inhibitor and the KRas G12C inhibitor are administered on the same day.
8. The method according to any one of claims 1-6, wherein the SOS1 inhibitor and the KRas G12C inhibitor are administered on different days.
9. The method according to any one of claims 1-8, wherein the KRas G12C inhibitor is administered at a maximum tolerated dose.
10. The method according to any one of claims 1-8, wherein the SOS1 inhibitor is administered at a maximum tolerated dose.
11. The method according to any one of claims 1-8, wherein the SOS1 inhibitor and the KRas G12C inhibitor are each administered at a maximum tolerated dose.
12. The method according to any one of claims 1-8, wherein the KRas G12C inhibitor is administered at below maximum tolerated dose.
13. The method according to any one of claims 1-8, wherein the SOS 1 inhibitor is administered at below maximum tolerated dose.
14. The method according to any one of claims 1-8, wherein the SOS1 inhibitor and the KRas G12C inhibitor are each administered at below maximum tolerated dose.
15. The method according to any one of claims 1-14, wherein the therapeutically effective amount of the combination of the SOS1 inhibitor and the KRas G12C inhibitor results in an increased duration of overall survival, an increased duration of progression free survival, an increase in tumor growth regression, an increase in tumor growth inhibition or an increased duration of stable disease in the subjects relative to treatment with only the KRas G12C inhibitor.
16. The method according to any one of claims 1-14, wherein the therapeutically effective amount of the combination of the SOS1 inhibitor and the KRas G12C inhibitor results in an increased duration of overall survival, an increased duration of progression free survival, an increase in tumor growth regression, an increase in tumor growth inhibition or an increased duration of stable disease in the subjects relative to treatment with only the SOS1 inhibitor.
17. A pharmaceutical composition, comprising a therapeutically effective amount of a combination of a SOS1 inhibitor and the KRas G12C inhibitor adagrasib according to any one of claims 1-14, and a pharmaceutically acceptable excipient.
18. A method for inhibiting KRas G12C activity in a cell, comprising contacting the cell in which inhibition of KRas G12C activity is desired with an effective amount of a combination of the KRas G12C inhibitor adagrasib: or a pharmaceutically acceptable salt thereof, and a SOS1 inhibitor.
19. The method according to claim 18, wherein the SOS1 inhibitor is selected from:
Me Me
Me
(f?)-2-methyl-3-(l-((4-methyl-7-morpholinopyrido[3,4-<i]pyridazin-l- yl)amino)ethyl)benzonitrile,
3 -(( R )- 1 -((7-((,S)-hexahydropyrazino[2, 1 -c] [ 1 ,4]oxazin-8(li7)-yl)-4-methylpyrido[3 ,4- 6/]pyridazin-l -yl)amino)ethyl)-2-methylbenzonitrile,
(7ί)-3-( 1 -((7-(3 -(dim ethyl ami no)-3 -methyl azetidin- 1 -yl )-4-rn ethyl pyrido[3,4-6/]pyridazin- l - yl)amino)ethyl)-2-methylbenzonitrile, and
Ms Me
(i?)-2-methyl-3-(l-((4-methyl-7-(4-methylpiperazin-l-yl)pyrido[3,4-<i]pyridazin-l- yl)amino)ethyl)benzonitrile, e
(i?)-3-( 1 -((7-(4-ethylpiperazin- 1 -yl)-4-mcthylpyrido| 3.4-£/|pyridazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile,
IVSe !V!e
(7Z)-2-mcthyl-3-( 1 -((4-methyl-7-(piperazin- 1 -yl)pyrido|3.4-£/|pyridazin- 1 -yl)amino)ethyl)benzonitrile, and
Me Me
3 -((//)- 1 -((7 -((.V)-3 -(dimethylamino)pyrrolidin- 1 -yl)-4-methylpyrido |3.4-£/|pyridazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile, and
Me Me
MeU
(R)- 3 -( 1 -((6-fluoro-4-methyl-7-(4-methylpiperazin- 1 -yl)phthalazin- 1 -yl)amino)ethyl)-2- methylbenzonitrile, and pharmaceutically acceptable salts thereof.
20. The method according to claim 18, wherein the SOS1 inhibitor is e
H
Ύ CN or a pharmaceutically acceptable salt thereof.
21 The method according to claim 20, further comprising contacting the cell with a compound having the following structure:
pharmaceutically acceptable salt thereof.
22. The method according to any one of claims 1-16 and 18-21, wherein the SOS1 inhibitor synergistically increases the sensitivity of cancer cells to the KRas G12C inhibitor.
23. A method for increasing the sensitivity of a cancer cell to the KRas G12C inhibitor comprising administering to a subject undergoing KRas G12C treatment with an effective amount of a combination the KRas G12C inhibitor adagrasib:
or a pharmaceutically acceptable salt thereof, and a SOS1 inhibitor, wherein the SOS1 inhibitor synergistically increases the sensitivity of the cancer cell to the KRas G12C inhibitor.
24. The method according to claim 23, wherein the SOS inhibitor is
pharmaceutically acceptable salt thereof.
25. The method according to claim 24, wherein the method further comprises administering to the subject in need thereof a compound with the following structure:
acceptable salt thereof.
26. The method according to any of claims 1-16 or 18-25, wherein the therapeutically effective amount of the KRas G12C inhibitor in the combination is between about 0.01 to 100 mg/kg per day.
27. The method according to claim 26, wherein the therapeutically effective amount of the KRas G12C inhibitor in the combination is between about 0.1 to 50 mg/kg per day.
28. The method according to any of claims 1-16 or 18-27, wherein the therapeutically effective amount of the SOS1 inhibitor in the combination is between about 0.01 to 100 mg/kg per day.
29. The method according to claim 28, wherein the therapeutically effective amount of the SOS1 inhibitor in the combination is between about 0.1 to 50 mg/kg per day.
30. The method according to any one of claims 1-16 and 18-29, wherein the cancer is selected from the group consisting of Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma,
adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial 'carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.
31. The method according to claim 30, wherein the cancer wherein the cancer is a KRas G12C-associated cancer.
32. The method according to claim 30, wherein the cancer is non-small cell lung cancer.
33. A kit comprising the pharmaceutical composition of claim 17 for treating KRas G12C cancer in a subject.
34. The kit according to claim 33, further comprising an insert with instructions for administration of the pharmaceutical composition(s).
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US202163194140P | 2021-05-27 | 2021-05-27 | |
US202263329056P | 2022-04-08 | 2022-04-08 | |
PCT/US2022/030697 WO2022251193A1 (en) | 2021-05-27 | 2022-05-24 | Combination therapies |
Publications (1)
Publication Number | Publication Date |
---|---|
EP4346826A1 true EP4346826A1 (en) | 2024-04-10 |
Family
ID=84229070
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP22811968.1A Pending EP4346826A1 (en) | 2021-05-27 | 2022-05-24 | Combination therapies |
Country Status (4)
Country | Link |
---|---|
US (1) | US20220395507A1 (en) |
EP (1) | EP4346826A1 (en) |
TW (1) | TW202313050A (en) |
WO (1) | WO2022251193A1 (en) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2023196218A2 (en) * | 2022-04-08 | 2023-10-12 | Mirati Therapeutics, Inc. | Combination therapies comprising a sos1 inhibitor and a mek inhibitor |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3878850A1 (en) * | 2016-12-22 | 2021-09-15 | Boehringer Ingelheim International GmbH | Novel benzylamino substituted quinazolines and derivatives as sos1 inhibitors |
AU2019401466A1 (en) * | 2018-12-21 | 2021-07-01 | Revolution Medicines, Inc. | Compounds that participate in cooperative binding and uses thereof |
EP4076418A4 (en) * | 2019-12-20 | 2024-01-24 | Mirati Therapeutics Inc | Sos1 inhibitors |
-
2022
- 2022-05-24 WO PCT/US2022/030697 patent/WO2022251193A1/en active Application Filing
- 2022-05-24 EP EP22811968.1A patent/EP4346826A1/en active Pending
- 2022-05-24 US US17/752,609 patent/US20220395507A1/en active Pending
- 2022-05-27 TW TW111119880A patent/TW202313050A/en unknown
Also Published As
Publication number | Publication date |
---|---|
US20220395507A1 (en) | 2022-12-15 |
WO2022251193A1 (en) | 2022-12-01 |
TW202313050A (en) | 2023-04-01 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR20210113587A (en) | combination therapy | |
JP2022500384A (en) | Combination therapy | |
EP3849536A1 (en) | Combination therapies | |
EP3849538A1 (en) | Combination therapies | |
EP3849534A1 (en) | Combination therapies | |
JP2022500388A (en) | Combination therapy | |
WO2023059598A1 (en) | Combination therapies of kras g12d inhibitors with shp-2 inhibitors | |
EP4346826A1 (en) | Combination therapies | |
WO2023059597A1 (en) | Combination therapies of kras g12d inhibitors with sos1 inhibitors | |
WO2023196218A2 (en) | Combination therapies comprising a sos1 inhibitor and a mek inhibitor | |
JP2024521788A (en) | Combination therapy | |
WO2022165142A1 (en) | Combination therapies | |
WO2023196086A2 (en) | Combination therapies comprising a sos1 inhibitor and an egfr inhibitor | |
CN117615762A (en) | Combination therapy | |
CA3233566A1 (en) | Combinations of kras g12d inhibitors with pi3ka inhibitors and related methods of treatment | |
WO2023059596A1 (en) | COMBINATION THERAPIES OF KRAS G12D INHIBITORS WITH Pan ErbB FAMILY INHIBITORS | |
KR20240073112A (en) | Combination of PI3Ka inhibitor and KRAS G12D inhibitor and related treatment methods | |
WO2024072931A2 (en) | Combination therapies |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20231130 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |